AVERAGE SALES PRICE (ASP) FOR MEDICARE ... - Janssen CNS

AVERAGE SALES PRICE (ASP) 

FOR MEDICARE DRUG PROGRAM 

3rd QUARTER 2010 UPDATE 

When RISPERDAL ® CONSTA ® is administered in a physician office and covered under 

Medicare Part B, it is reimbursed based on Average Sales Price (ASP) + 6% 1 

• ASP is based on quarterly sales data provided by manufacturers 2 

• ASP = Gross Sales - (Discounts + Chargebacks + Rebates) 2 

Total Number of Units Sold 

• Manufacturers submit ASP data to Centers for Medicare & Medicaid Services (CMS) by specific 

deadlines following the end of each quarterly period. CMS uses this data to determine the Medicare 

reimbursement rate for the subsequent quarter. This results in a 2 quarter lag between the quarter in 

which the sales occur and the time when the sales are reflected in a revised reimbursement rate. For 

example, 1st quarter sales become the basis for 3rd quarter reimbursement. 3 

3rd QUARTER 2010 RISPERDAL ® CONSTA ® MEDICARE ALLOWABLE 4 

Permanent 

HCPCS Code 

Short Description 2010 Medicare Allowable 

J2794 5 Risperidone, long acting, 0.5 mg ASP + 6% 

Note: J2794 is reported per 0.5-mg unit 

RISPERDAL ® 

CONSTA ® 

# of 

Units 

3rd Qtr 2010 

Medicare 

Allowable *†‡ 

In 2010, Medicare will reimburse for separately payable, non-pass-through drugs such as RISPERDAL ® CONSTA ® administered in 

Medicare-participating hospital outpatient departments based on ASP+4%. 6 

The fact that a drug, device, procedure, or service is assigned a HCPCS code and a payment rate under the Medicare Physician Fee Schedule (MPFS), does not imply 

coverage by the Medicare program, but indicates only how the product, procedure, or service may be paid if covered by the program. Fiscal Intermediaries (FIs)/ 

Medicare Administrative Contractors (MACs) determine whether a drug, device, procedure, or other service meets all program requirements for coverage. 

Reference: CMS Manual System, Coverage Determinations. 

RISPERDAL ® CONSTA ® is available in 12.5-, 25-, 37.5-, and 50-mg vials. Dose should be given in its entirety. 

If you have coverage or coding questions related to RISPERDAL ® CONSTA ® , please call the CONSTANTAccess helpline toll-free: (877) 747-7524. 

The information contained in this document is provided for informational purposes only and represents no statement, promise, or guarantee 

by Ortho-McNeil-Janssen Pharmaceuticals, Inc. concerning levels of reimbursement, payment, or charge. Similarly, all HCPCS codes are 

supplied for informational purposes only and represent no statement, promise, or guarantee by Ortho-McNeil-Janssen Pharmaceuticals, Inc. 

that these codes will be appropriate or that reimbursement will be made. It is not intended to increase or maximize reimbursement by any 

payer. We strongly recommend that you consult the payer organization with regard to its reimbursement policies. 

* Calculated Medicare allowable rate may change quarterly based on manufacturer data from the quarter before last. 

† 3rd Quarter Medicare Allowable = $5.055 per 0.5 mg. 4 

‡ Certain Medicare Carriers may apply the Mental Health Treatment Limitation for physician office/CMHC services in which Medicare payment will be a 

portion of the Medicare allowable rate. 7 

§ Patients may also be eligible for supplemental coverage by state Medicaid. 

References: 1. 42 CFR § 414.904. 2. 42 CFR § 414.804. 3. 42 USC 1395w-3a 4. http://www.cms.hhs.gov/McrPartBDrugAvgSalesPrice/01a19_2010aspfiles.asp#TopOfPage 

5. 2010 HCPCS Level II Expert. Eden Prairie, MN: Ingenix; 2009. 6. 74 Fed. Reg. 223, 60527 (Nov. 20, 2009) 7. 42 CFR § 410.155. 

Please see Important Safety Information, including Boxed Warning, on reverse side. 

Please see accompanying full Prescribing Information. 

= 

3rd Qtr 2010 

Co-Insurance § 

+ 

3rd Qtr 2010 

Medicare 

Payment ‡ 

12.5-mg injection 25 $126.38 $25.28 $101.10 

25-mg injection 50 $252.75 $50.55 $202.20 

37.5-mg injection 75 $379.13 $75.83 $303.30 

50-mg injection 100 $505.50 $101.10 $404.40

RISPERDAL ® CONSTA ® (risperidone) long-acting injection is indicated for the treatment of schizophrenia and for the maintenance treatment of 

Bipolar I Disorder. 

IMPORTANT SAFETY INFORMATION FOR RISPERDAL ® CONSTA ® (risperidone) 

WARNING: Increased Mortality in Elderly Patients with Dementia-Related Psychosis 

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 

17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk 

of death in the drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a 

typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the 

placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, 

sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, 

treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in 

observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. 

RISPERDAL ® CONSTA ® is not approved for the treatment of patients with dementia-related psychosis. 

Contraindications: RISPERDAL ® CONSTA ® is contraindicated in patients with a known hypersensitivity to the product. 

Cerebrovascular Adverse Events (CAEs): CAEs (e.g., stroke, transient ischemia attacks), including fatalities, were reported in placebo-controlled trials in elderly 

patients with dementia-related psychosis taking oral risperidone. The incidence of CAEs was significantly higher than with placebo. RISPERDAL ® CONSTA ® is not 

approved for the treatment of patients with dementia-related psychosis. 

Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with the use of antipsychotic medications. Clinical 

manifestations include muscle rigidity, fever, altered mental status, and evidence of autonomic instability (see full Prescribing Information). Management should 

include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and close medical 

monitoring, and treatment of any concomitant serious medical problems. 

Tardive Dyskinesia (TD): TD is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic 

medications. The risk of developing TD and the likelihood that dyskinetic movements will become irreversible are believed to increase with duration of treatment 

and total cumulative dose, but can develop after relatively brief treatment at low doses. Elderly women patients appeared to be at increased risk for TD, although 

it is impossible to predict which patients will develop the syndrome. Prescribing should be consistent with the need to minimize the risk of TD (see full Prescribing 

Information). Discontinue drug if clinically appropriate. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. 

Hyperglycemia and Diabetes: Hyperglycemia, some cases extreme and associated with ketoacidosis, hyperosmolar coma or death has been reported in 

patients treated with atypical antipsychotics (APS), including RISPERDAL ® CONSTA ® . Patients starting treatment with APS who have or are at risk for diabetes 

mellitus should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia should also 

undergo fasting blood glucose testing. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. Some patients 

require continuation of anti-diabetic treatment despite discontinuation of the suspect drug. 

Hyperprolactinemia: As with other drugs that antagonize dopamine D 2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic 

administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents. 

Orthostatic Hypotension and Syncope: RISPERDAL ® CONSTA ® may induce orthostatic hypotension associated with dizziness, tachycardia, and in some 

patients, syncope, especially during the initial dose-titration period. RISPERDAL ® CONSTA ® should be used with caution in patients with known cardiovascular 

disease (e.g., heart failure, history of MI or ischemia, conduction abnormalities), cerebrovascular disease or conditions that would predispose patients to hypotension 

(e.g., dehydration, hypovolemia) and additionally elderly patients with renal or hepatic impairment. Monitoring should be considered in patients for whom this may be 

of concern. 

Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including RISPERDAL ® CONSTA ® . Patients with a history of clinically 

significant low white blood cell count (WBC) or drug-induced leukopenia/neutropenia should have frequent complete blood cell counts during the first few months 

of therapy. At the first sign of a clinically significant decline in WBC, and in the absence of other causative factors, discontinuation of RISPERDAL ® CONSTA ® should 

be considered. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if 

such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count

RISPERDAL ® CONSTA ® 

(risperidone) LONG-ACTING INJECTION 

HIGHLIGHTS OF PRESCRIBING INFORMATION 

These highlights do not include all the information needed to use 

RISPERDAL ® CONSTA ® safely and effectively. See full prescribing information for 

RISPERDAL ® CONSTA ® . 

RISPERDAL ® CONSTA ® (risperidone) LONG-ACTING INJECTION 

Initial U.S. Approval: 2003 

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA- 

RELATED PSYCHOSIS 

See full prescribing information for complete boxed warning. 

Elderly patients with dementia-related psychosis treated with antipsychotic 

drugs are at an increased risk of death. RISPERDAL ® CONSTA ® is not approved 

for use in patients with dementia-related psychosis. (5.1) 

-----------------------------------RECENT MAJOR CHANGES ------------------------------ 

Indications and Usage, Bipolar Disorder (1.2) May 2009 

Dosage and Administration, Bipolar Disorder (2.2) May 2009 

Warnings and Precautions, Leukopenia, Neutropenia, 

and Agranulocytosis (5.8) July 2009 

Warnings and Precautions, Suicide (5.17) May 2009 

---------------------------------INDICATIONS AND USAGE---------------------------------- 

RISPERDAL ® CONSTA ® is an atypical antipsychotic indicated: 

• for the treatment of schizophrenia. (1.1) 

• as monotherapy or as adjunctive therapy to lithium or valproate for the 

maintenance treatment of Bipolar I Disorder. (1.2) 

--------------------------------DOSAGE AND ADMINISTRATION--------------------------- 

• For patients who have never taken oral RISPERDAL ® , tolerability should 

be established with oral RISPERDAL ® prior to initiating treatment with 

RISPERDAL ® CONSTA ® . (2) 

• Administer by deep intramuscular (IM) deltoid or gluteal injection. Each injection 

should be administered by a health care professional using the appropriate 

enclosed safety needle (1-inch for deltoid administration alternating injections 

between the two arms and 2-inch for gluteal administration alternating 

injections between the two buttocks). Do not administer intravenously. (2) 

• 25 mg intramuscular (IM) every 2 weeks. Patients not responding to 25 mg may 

benefit from a higher dose of 37.5 mg or 50 mg. The maximum dose should not 

exceed 50 mg every 2 weeks. (2) 

• Oral RISPERDAL ® (or another antipsychotic medication) should be given with 

the first injection of RISPERDAL ® CONSTA ® , and continued for 3 weeks (and 

then discontinued) to ensure adequate therapeutic plasma concentrations from 

RISPERDAL ® CONSTA ® . (2) 

• Upward dose adjustment of RISPERDAL ® CONSTA ® should not be made more 

frequently than every 4 weeks. Clinical effects of each upward dose adjustment 

should not be anticipated earlier than 3 weeks after injection. (2) 

• Avoid inadvertent administration into a blood vessel. (5.15) 

• See Full Prescribing Information Section 2.8 for instructions for use. 

-------------------------------DOSAGE FORMS AND STRENGTHS-------------------------- 

Vial kits: 12.5 mg, 25 mg, 37.5 mg, and 50 mg (3) 

-------------------------------------CONTRAINDICATIONS------------------------------------ 

• Known hypersensitivity to the product (4) 

------------------------------WARNINGS AND PRECAUTIONS------------------------------ 

• Cerebrovascular events, including stroke, in elderly patients with dementiarelated 

psychosis. RISPERDAL ® CONSTA ® is not approved for use in patients 

with dementia-related psychosis (5.2) 

• Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and 

close monitoring (5.3) 

• Tardive Dyskinesia: Discontinue treatment if clinically appropriate (5.4) 

• Hyperglycemia and Diabetes Mellitus- in some cases extreme and associated 

with ketoacidosis or hyperosmolar coma or death, has been reported in patients 

taking risperidone. Patients with diabetes mellitus should have glucose levels 

monitored regularly. Patients with risk factors for diabetes mellitus should 

undergo fasting glucose testing at the beginning of treatment and periodically 

during treatment. All patients taking risperidone should be monitored for 

symptoms of hyperglycemia. Symptomatic patients should undergo fasting 

glucose testing. (5.5) 

• Hyperprolactinemia: Risperidone treatment may elevate prolactin levels. 

Long-standing hyperprolactinemia, when associated with hypogonadism, can 

lead to decreased bone density in men and women. (5.6) 

• Orthostatic hypotension: associated with dizziness, tachycardia, bradycardia, and 

syncope can occur, especially during initial dose titration with oral risperidone. 

Use caution in patients with cardiovascular disease, cerebrovascular disease, 

and conditions that could affect hemodynamic responses. (5.7) 

RISPERDAL ® CONSTA ® (risperidone) LONG-ACTING INJECTION 

• Leukopenia, Neutropenia, and Agranulocytosis have been reported with 

antipsychotics, including RISPERDAL ® CONSTA ® . Patients with history of a 

clinically significant low white blood cell count (WBC) or a drug-induced 

leukopenia/neutropenia should have their complete blood cell count (CBC) 

monitored frequently during the first few months of therapy and discontinuation 

of RISPERDAL ® CONSTA ® should be considered at the first sign of a clinically 

significant decline in WBC in the absence of other causative factors. (5.8) 

• Potential for cognitive and motor impairment: has potential to impair judgment, 

thinking, and motor skills. Use caution when operating machinery, including 

automobiles. (5.9) 

• Seizures: Use cautiously in patients with a history of seizures or with conditions 

that potentially lower the seizure threshold. (5.10) 

• Dysphagia: Esophageal dysmotility and aspiration can occur. Use cautiously in 

patients at risk for aspiration pneumonia. (5.11) 

• Priapism: has been reported. Severe priapism may require surgical intervention. 

(5.12) 

• Thrombotic Thrombocytopenic Purpura (TTP): has been reported. (5.13) 

• Avoid inadvertent administration into a blood vessel (5.15) 

• Suicide: There is increased risk of suicide attempt in patients with schizophrenia 

or bipolar disorder, and close supervision of high-risk patients should 

accompany drug therapy. (5.17) 

• Increased sensitivity in patients with Parkinson’s disease or those with dementia 

with Lewy bodies: has been reported. Manifestations include mental status 

changes, motor impairment, extrapyramidal symptoms, and features consistent 

with Neuroleptic Malignant Syndrome. (5.18) 

• Diseases or conditions that could affect metabolism or hemodynamic responses: 

Use with caution in patients with such medical conditions (e.g., recent 

myocardial infarction or unstable cardiac disease) (5.18) 

-------------------------------------ADVERSE REACTIONS------------------------------------ 

The most common adverse reactions in clinical trials in patients with schizophrenia 

(≥ 5%) were headache, parkinsonism, dizziness, akathisia, fatigue, constipation, 

dyspepsia, sedation, weight increased, pain in extremity, and dry mouth. The most 

common adverse reactions in clinical trials in patients with bipolar disorder were 

weight increased (5% in monotherapy trial) and tremor and parkinsonism ( ≥ 10% in 

adjunctive therapy trial). (6) 

The most common adverse reactions that were associated with discontinuation 

from clinical trials in patients with schizophrenia were agitation, depression, 

anxiety, and akathisia. Adverse reactions that were associated with discontinuation 

from bipolar disorder trials were hyperglycemia (one subject monotherapy trial) 

and hypokinesia and tardive dyskinesia (one subject each in adjunctive therapy 

trial). (6) 

To report SUSPECTED ADVERSE REACTIONS, contact Janssen, Division of 

Ortho-McNeil-Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or 

FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 

-------------------------------------DRUG INTERACTIONS------------------------------------ 

• Due to CNS effects, use caution when administering with other centrally-acting 

drugs. Avoid alcohol. (7.1) 

• Due to hypotensive effects, hypotensive effects of other drugs with this potential 

may be enhanced. (7.2) 

• Effects of levodopa and dopamine agonists may be antagonized. (7.3) 

• Cimetidine and ranitidine increase the bioavailability of risperidone. (7.5) 

• Clozapine may decrease clearance of risperidone. (7.6) 

• Fluoxetine and paroxetine increase plasma concentrations of risperidone. (7.11) 

• Carbamazepine and other enzyme inducers decrease plasma concentrations of 

risperidone. (7.12) 

--------------------------------USE IN SPECIFIC POPULATIONS----------------------------- 

• Renal or Hepatic Impairment: dose appropriately with oral RISPERDAL ® prior to 

initiating treatment with RISPERDAL ® CONSTA ® . A lower starting dose of 

RISPERDAL ® CONSTA ® of 12.5 mg may be appropriate in some patients. (2.4) 

• Nursing Mothers: should not breast feed. (8.3) 

• Pediatric Use: safety and effectiveness not established in patients less than 

18 years of age. (8.4) 

• Elderly: dosing for otherwise healthy elderly patients is the same as for healthy 

nonelderly. Elderly may be more predisposed to orthostatic effects than 

nonelderly. (8.5) 

See 17 for PATIENT COUNSELING INFORMATION. 

Revised: 04/2010 

FULL PRESCRIBING INFORMATION: CONTENTS* 

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH 

DEMENTIA-RELATED PSYCHOSIS 

1 INDICATIONS AND USAGE 

1.1 Schizophrenia 

1.2 Bipolar Disorder 

2 DOSAGE AND ADMINISTRATION 



2.3 General Dosing Information 

2.4 Dosage in Special Populations 

2.5 Reinitiation of Treatment in Patients Previously Discontinued

RISPERDAL ® CONSTA ® (risperidone) LONG-ACTING INJECTION RISPERDAL ® CONSTA ® (risperidone) LONG-ACTING INJECTION 

2.6 Switching from Other Antipsychotics 

2.7 Co-Administration of RISPERDAL ® CONSTA ® with Certain Other 

Medications 

2.8 Instructions for Use 

3 DOSAGE FORMS AND STRENGTHS 

4 CONTRAINDICATIONS 

5 WARNINGS AND PRECAUTIONS 

5.1 Increased Mortality in Elderly Patients with Dementia-Related 

Psychosis 

5.2 Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients 

with Dementia-Related Psychosis 

5.3 Neuroleptic Malignant Syndrome (NMS) 

5.4 Tardive Dyskinesia 

5.5 Hyperglycemia and Diabetes Mellitus 

5.6 Hyperprolactinemia 

5.7 Orthostatic Hypotension 

5.8 Leukopenia, Neutropenia, and Agranulocytosis 

5.9 Potential for Cognitive and Motor Impairment 

5.10 Seizures 

5.11 Dysphagia 

5.12 Priapism 

5.13 Thrombotic Thrombocytopenic Purpura (TTP) 

5.14 Body Temperature Regulation 

5.15 Administration 

5.16 Antiemetic Effect 

5.17 Suicide 

5.18 Use in Patients with Concomitant Illness 

5.19 Osteodystrophy and Tumors in Animals 

5.20 Monitoring: Laboratory Tests 

6 ADVERSE REACTIONS 

6.1 Commonly-Observed Adverse Reactions in Double-Blind, 

Placebo-Controlled Clinical Trials - Schizophrenia 

6.2 Commonly-Observed Adverse Reactions in Double-Blind, 

Placebo-Controlled Clinical Trials – Bipolar Disorder 

6.3 Other Adverse Reactions Observed During the Premarketing Evaluation 

of RISPERDAL ® CONSTA ® 

6.4 Discontinuations Due to Adverse Reactions 

6.5 Dose Dependency of Adverse Reactions in Clinical Trials 

6.6 Changes in Body Weight 

6.7 Changes in ECG 

6.8 Pain Assessment and Local Injection Site Reactions 

6.9 Postmarketing Experience 

7 DRUG INTERACTIONS 

7.1 Centrally-Acting Drugs and Alcohol 

7.2 Drugs with Hypotensive Effects 

7.3 Levodopa and Dopamine Agonists 

7.4 Amitriptyline 

7.5 Cimetidine and Ranitidine 

7.6 Clozapine 

7.7 Lithium 

7.8 Valproate 

7.9 Digoxin 

7.10 Topiramate 

7.11 Drugs That Inhibit CYP 2D6 and Other CYP Isozymes 

7.12 Carbamazepine and Other CYP 3A4 Enzyme Inducers 

7.13 Drugs Metabolized by CYP 2D6 

8 USE IN SPECIFIC POPULATIONS 

8.1 Pregnancy 

8.2 Labor and Delivery 

8.3 Nursing Mothers 

8.4 Pediatric Use 

8.5 Geriatric Use 

9 DRUG ABUSE AND DEPENDENCE 

9.1 Controlled Substance 

9.2 Abuse 

9.3 Dependence 

10 OVERDOSAGE 

10.1 Human Experience 

10.2 Management of Overdosage 

11 DESCRIPTION 

12 CLINICAL PHARMACOLOGY 

12.1 Mechanism of Action 

12.2 Pharmacodynamics 

12.3 Pharmacokinetics 

13 NONCLINICAL TOXICOLOGY 

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 

14 CLINICAL STUDIES 


14.2 Bipolar Disorder - Monotherapy 

14.3 Bipolar Disorder - Adjunctive Therapy 

16 HOW SUPPLIED/STORAGE AND HANDLING 

17 PATIENT COUNSELING INFORMATION 


17.2 Interference with Cognitive and Motor Performance 

17.3 Pregnancy 

17.4 Nursing 

17.5 Concomitant Medication 

17.6 Alcohol 

*Sections or subsections omitted from the full prescribing information are not listed 

FULL PRESCRIBING INFORMATION 

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA- 

RELATED PSYCHOSIS 

Elderly patients with dementia-related psychosis treated with antipsychotic 

drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials 

(modal duration of 10 weeks), largely in patients taking atypical antipsychotic 

drugs, revealed a risk of death in drug-treated patients of between 1.6 to 

1.7 times the risk of death in placebo-treated patients. Over the course of a 

typical 10-week controlled trial, the rate of death in drug-treated patients was 

about 4.5%, compared to a rate of about 2.6% in the placebo group. Although 

the causes of death were varied, most of the deaths appeared to be either 

cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) 

in nature. Observational studies suggest that, similar to atypical antipsychotic 

drugs, treatment with conventional antipsychotic drugs may increase mortality. 

The extent to which the findings of increased mortality in observational studies 

may be attributed to the antipsychotic drug as opposed to some characteristic(s) 

of the patients is not clear. RISPERDAL ® CONSTA ® (risperidone) is not approved 

for the treatment of patients with dementia-related psychosis. [See Warnings 

and Precautions (5.1)] 

1 INDICATIONS AND USAGE 


RISPERDAL ® CONSTA ® (risperidone) is indicated for the treatment of schizophrenia 

[see Clinical Studies (14.1)]. 


RISPERDAL ® CONSTA ® is indicated as monotherapy or as adjunctive therapy to 

lithium or valproate for the maintenance treatment of Bipolar I Disorder [see Clinical 

Studies (14.2, 14.3)]. 

2 DOSAGE AND ADMINISTRATION 

For patients who have never taken oral RISPERDAL ® , it is recommended to 

establish tolerability with oral RISPERDAL ® prior to initiating treatment with 


RISPERDAL ® CONSTA ® should be administered every 2 weeks by deep intramuscular 

(IM) deltoid or gluteal injection. Each injection should be administered by a health 

care professional using the appropriate enclosed safety needle [see Dosage and 

Administration (2.8)]. For deltoid administration, use the 1-inch needle alternating 

injections between the two arms. For gluteal administration, use the 2-inch needle 

alternating injections between the two buttocks. Do not administer intravenously. 


The recommended dose for the treatment of schizophrenia is 25 mg IM every 

2 weeks. Although dose response for effectiveness has not been established for 

RISPERDAL ® CONSTA ® , some patients not responding to 25 mg may benefit from a 

higher dose of 37.5 mg or 50 mg. The maximum dose should not exceed 50 mg 

RISPERDAL ® CONSTA ® every 2 weeks. No additional benefit was observed with 

dosages greater than 50 mg RISPERDAL ® CONSTA ® ; however, a higher incidence 

of adverse effects was observed. 

The efficacy of RISPERDAL ® CONSTA ® in the treatment of schizophrenia has not 

been evaluated in controlled clinical trials for longer than 12 weeks. Although 

controlled studies have not been conducted to answer the question of how long 

patients with schizophrenia should be treated with RISPERDAL ® CONSTA ® , oral 

risperidone has been shown to be effective in delaying time to relapse in longer-term 

use. It is recommended that responding patients be continued on treatment with 

RISPERDAL ® CONSTA ® at the lowest dose needed. The physician who elects to 

use RISPERDAL ® CONSTA ® for extended periods should periodically re-evaluate 

the long-term risks and benefits of the drug for the individual patient. 


The recommended dose for monotherapy or adjunctive therapy to lithium or 

valproate for the maintenance treatment of Bipolar I Disorder is 25 mg IM every 

2 weeks. Some patients may benefit from a higher dose of 37.5 mg or 50 mg. 

Dosages above 50 mg have not been studied in this population. The physician who 

elects to use RISPERDAL ® CONSTA ® for extended periods should periodically 

re-evaluate the long-term risks and benefits of the drug for the individual patient. 

2.3 General Dosing Information 

A lower initial dose of 12.5 mg may be appropriate when clinical factors warrant 

dose adjustment, such as in patients with hepatic or renal impairment, for certain 

drug interactions that increase risperidone plasma concentrations [see Drug 

Interactions (7.11)] or in patients who have a history of poor tolerability to 

psychotropic medications. The efficacy of the 12.5 mg dose has not been investigated 

in clinical trials.


Oral RISPERDAL ® (or another antipsychotic medication) should be given with the 

first injection of RISPERDAL ® CONSTA ® and continued for 3 weeks (and then 

discontinued) to ensure that adequate therapeutic plasma concentrations are 

maintained prior to the main release phase of risperidone from the injection site 

[see Clinical Pharmacology (12.3)]. 

Upward dose adjustment should not be made more frequently than every 4 weeks. 

The clinical effects of this dose adjustment should not be anticipated earlier than 

3 weeks after the first injection with the higher dose. 

In patients with clinical factors such as hepatic or renal impairment or certain drug 

interactions that increase risperidone plasma concentrations [see Drug Interactions 

(7.11)], dose reduction as low as 12.5 mg may be appropriate. The efficacy of the 

12.5 mg dose has not been investigated in clinical trials. 

Do not combine two different dose strengths of RISPERDAL ® CONSTA ® in a single 

administration. 

2.4 Dosage in Special Populations 

Elderly 

For elderly patients treated with RISPERDAL ® CONSTA ® , the recommended dosage 

is 25 mg IM every 2 weeks. Oral RISPERDAL ® (or another antipsychotic medication) 

should be given with the first injection of RISPERDAL ® CONSTA ® and should be 

continued for 3 weeks to ensure that adequate therapeutic plasma concentrations 

are maintained prior to the main release phase of risperidone from the injection site 

[see Clinical Pharmacology (12.3)]. 

Renal or Hepatic Impairment 

Patients with renal or hepatic impairment should be treated with titrated doses of oral 

RISPERDAL ® prior to initiating treatment with RISPERDAL ® CONSTA ® . The 

recommended starting dose is 0.5 mg oral RISPERDAL ® twice daily during the first 

week, which can be increased to 1 mg twice daily or 2 mg once daily during the 

second week. If a total daily dose of at least 2 mg oral RISPERDAL ® is well tolerated, 

an injection of 25 mg RISPERDAL ® CONSTA ® can be administered every 2 weeks. 

Oral supplementation should be continued for 3 weeks after the first injection until 

the main release of risperidone from the injection site has begun. In some patients, 

slower titration may be medically appropriate. Alternatively, a starting dose of 

RISPERDAL ® CONSTA ® of 12.5 mg may be appropriate. The efficacy of the 12.5 mg 

dose has not been investigated in clinical trials. 

Patients with renal impairment may have less ability to eliminate risperidone than 

normal adults. Patients with impaired hepatic function may have an increase in the 

free fraction of the risperidone, possibly resulting in an enhanced effect [see Clinical 

Pharmacology (12.3)]. Elderly patients and patients with a predisposition to 

hypotensive reactions or for whom such reactions would pose a particular risk 

should be instructed in nonpharmacologic interventions that help to reduce the 

occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for 

several minutes before attempting to stand in the morning and slowly rising from a 

seated position). These patients should avoid sodium depletion or dehydration, and 

circumstances that accentuate hypotension (alcohol intake, high ambient 

temperature, etc.). Monitoring of orthostatic vital signs should be considered [see 

Warnings and Precautions (5.7)]. 

2.5 Reinitiation of Treatment in Patients Previously Discontinued 

There are no data to specifically address reinitiation of treatment. When restarting 

patients who have had an interval off treatment with RISPERDAL ® CONSTA ® , 

supplementation with oral RISPERDAL ® (or another antipsychotic medication) 

should be administered. 

2.6 Switching from Other Antipsychotics 

There are no systematically collected data to specifically address switching patients 

from other antipsychotics to RISPERDAL ® CONSTA ® , or concerning concomitant 

administration with other antipsychotics. Previous antipsychotics should be 

continued for 3 weeks after the first injection of RISPERDAL ® CONSTA ® to ensure 

that therapeutic concentrations are maintained until the main release phase of 

risperidone from the injection site has begun [see Clinical Pharmacology (12.3)]. 

For patients who have never taken oral RISPERDAL ® , it is recommended to 

establish tolerability with oral RISPERDAL ® prior to initiating treatment with 

RISPERDAL ® CONSTA ® . As recommended with other antipsychotic medications, 

the need for continuing existing EPS medication should be re-evaluated periodically. 

2.7 Co-Administration of RISPERDAL ® CONSTA ® with Certain Other 

Medications 

Co-administration of carbamazepine and other CYP 3A4 enzyme inducers (e.g., 

phenytoin, rifampin, phenobarbital) with risperidone would be expected to cause 

decreases in the plasma concentrations of the sum of risperidone and 

9-hydroxyrisperidone combined, which could lead to decreased efficacy of 

RISPERDAL ® CONSTA ® treatment. The dose of risperidone needs to be titrated 

accordingly for patients receiving these enzyme inducers, especially during 

initiation or discontinuation of therapy with these inducers [see Drug Interactions 

(7.11)]. At the initiation of therapy with carbamazepine or other known CYP 3A4 

hepatic enzyme inducers, patients should be closely monitored during the first 

4-8 weeks, since the dose of RISPERDAL ® CONSTA ® may need to be adjusted. A dose 

increase, or additional oral RISPERDAL ® , may need to be considered. On 

discontinuation of carbamazepine or other CYP 3A4 hepatic enzyme inducers, the 

dosage of RISPERDAL ® CONSTA ® should be re-evaluated and, if necessary, 

decreased. Patients may be placed on a lower dose of RISPERDAL ® CONSTA ® 

between 2 to 4 weeks before the planned discontinuation of carbamazepine or other 

CYP 3A4 inducers to adjust for the expected increase in plasma concentrations of 

risperidone plus 9-hydroxyrisperidone. For patients treated with the recommended 

dose of 25 mg RISPERDAL ® CONSTA ® and discontinuing from carbamazepine or other 

CYP3A4 enzyme inducers, it is recommended to continue treatment with the 25-mg 

dose unless clinical judgment necessitates lowering the RISPERDAL ® CONSTA ® dose 

to 12.5 mg or necessitates interruption of RISPERDAL ® CONSTA ® treatment. The 

efficacy of the12.5 mg dose has not been investigated in clinical trials. 

Fluoxetine and paroxetine, CYP 2D6 inhibitors, have been shown to increase the 

plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold respectively. Fluoxetine 

did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine 

lowered the concentration of 9-hydroxyrisperidone by about 10%. The dose of 

risperidone needs to be titrated accordingly when fluoxetine or paroxetine is 

co-administered. When either concomitant fluoxetine or paroxetine is initiated or 

discontinued, the physician should re-evaluate the dose of RISPERDAL ® CONSTA ® . 

When initiation of fluoxetine or paroxetine is considered, patients may be placed 

on a lower dose of RISPERDAL ® CONSTA ® between 2 to 4 weeks before the planned 

start of fluoxetine or paroxetine therapy to adjust for the expected increase in 

plasma concentrations of risperidone. When fluoxetine or paroxetine is initiated in 

patients receiving the recommended dose of 25 mg RISPERDAL ® CONSTA ® , it is 

recommended to continue treatment with the 25 mg dose unless clinical judgment 

necessitates lowering the RISPERDAL ® CONSTA ® dose to 12.5 mg or necessitates 

interruption of RISPERDAL ® CONSTA ® treatment. When RISPERDAL ® CONSTA ® is 

initiated in patients already receiving fluoxetine or paroxetine, a starting dose of 

12.5 mg can be considered. The efficacy of the 12.5 mg dose has not been 

investigated in clinical trials. The effects of discontinuation of concomitant 

fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 

9-hydroxyrisperidone have not been studied. [See Drug Interactions (7.11)] 

2.8 Instructions for Use 

Dose pack components include: 

RISPERDAL ® CONSTA ® must be reconstituted only in the diluent supplied in 

the dose pack, and must be administered with only the appropriate needle 

supplied in the dose pack for gluteal (2-inch needle) or deltoid (1-inch needle) 

administration. All components are required for administration. Do not 

substitute any components of the dose pack. To assure that the intended dose 

of risperidone is delivered, the full contents from the vial must be administered. 

Administration of partial contents may not deliver the intended dose of 

risperidone. 

Remove the dose pack of RISPERDAL ® CONSTA ® from the refrigerator and allow it 

to come to room temperature prior to reconstitution. 

1. Flip off the plastic colored cap from the vial. 

2. Peel back the blister pouch and 

remove the SmartSite ® Needle- 

Free Vial Access Device by 

holding the white luer cap. Do not 

touch the spike tip of the access 

device at any time. 

3. Place vial on a hard surface. Hold the base of the vial. 

Orient the SmartSite ® Access Device vertically over the 

vial so that the spike tip is at the center of the vial’s 

rubber stopper. With a straight downward push, press 

the spike tip of the SmartSite ® Access Device through 

the center of the vial’s rubber stopper until the device 

securely snaps onto the vial top. 

4. Swab the syringe connection point (blue circle) of the 

SmartSite ® Access Device with preferred antiseptic 

prior to attaching the syringe to the SmartSite ® Access 

Device.


5. The prefilled syringe has a white tip consisting of 2 

parts: a white collar and a smooth white cap. To open 

the syringe, hold the syringe by the white collar and 

snap off the smooth white cap (DO NOT TWIST OFF 

THE WHITE CAP). Remove the white cap together with 

the rubber tip cap inside. 

For all syringe assembly steps, hold the syringe only by 

the white collar located at the tip of the syringe. Be 

careful to not overtighten components when assembling. 

Overtightening connections may cause syringe 

component parts to loosen from the syringe body. 

6. While holding the white collar of the syringe, insert 

and press the syringe tip into the blue circle of the 

SmartSite ® Access Device and twist in a clockwise 

motion to secure the connection of the syringe to the 

SmartSite ® Access Device (avoid over-twisting). Hold 

the skirt of the SmartSite ® Access Device during 

attachment to prevent it from spinning. Keep the 

syringe and SmartSite ® Access Device aligned. 

7. Inject the entire contents of the syringe containing the 

diluent into the vial. 

8. Shake the vial vigorously while holding the plunger rod 

down with the thumb for a minimum of 10 seconds to 

ensure a homogeneous suspension. When properly 

mixed, the suspension appears uniform, thick, and 

milky in color. The microspheres will be visible in liquid, 

but no dry microspheres remain. 

9. Do not store the vial after reconstitution or the 

suspension may settle. If 2 minutes pass before 

injection, re-suspend by shaking vigorously. 

10. Invert the vial completely and slowly withdraw the 

suspension from the vial into the syringe. Tear section 

of the vial label at the perforation and apply detached 

label to syringe for identification purposes. 

11. While holding the white collar of the syringe, unscrew 

the syringe from the SmartSite ® Access Device. 

Discard both the vial and vial access device 

appropriately. 

12. Select the appropriate needle: 

For GLUTEAL injection, select the 20G TW 2-inch 

needle (longer needle with yellow colored hub in 

blister with yellow print) 

For DELTOID injection, select the 21G UTW 1-inch 

needle (shorter needle with green colored hub in 

blister with green print) 

13. Peel the blister pouch of the Needle-Pro ® safety 

device open halfway. Grasp the transparent needle 

sheath using the plastic peel pouch. To prevent 

contamination, be careful not to touch the orange 

Needle-Pro ® safety device’s Luer connector. While 

holding the white collar of the syringe, attach the Luer 

connection of the orange Needle-Pro ® safety device 

to the syringe with an easy clockwise twisting motion. 

14. While continuing to hold the white collar of the 

syringe, grasp the transparent needle sheath and seat 

the needle firmly on the orange Needle-Pro ® safety 

device with a push and a clockwise twist. 

15. If 2 minutes pass before injection, re-suspend by 

shaking vigorously. 

16. While holding the white collar of the syringe, pull the 

transparent needle sheath straight away from the 

needle. DO NOT TWIST the sheath as the Luer 

connections may be loosened. 

17. Tap the syringe gently to make any air bubbles rise to 

the top. Remove air in syringe by depressing the 

plunger rod while holding the needle in an upright 

position. Inject the entire contents of the syringe 

intramuscularly (IM) into the selected gluteal or deltoid 

muscle of the patient within 2 minutes to avoid settling. 

Gluteal injection should be made into the upper-outer 

quadrant of the gluteal area. DO NOT ADMINISTER 

INTRAVENOUSLY. 

WARNING: To avoid a needle stick injury with a contaminated needle: 

• Do not use free hand to press the Needle-Pro ® safety device over the needle. 

• Do not intentionally disengage the Needle-Pro ® safety device. 

• Do not attempt to straighten the needle or engage Needle-Pro ® safety device if 

the needle is bent or damaged. 

• Do not mishandle the Needle-Pro ® safety device, as it may cause the needle to 

protrude from the Needle-Pro ® safety device. 

18. After injection is complete, 

press the needle into the 

orange Needle-Pro ® safety 

device using a one-handed 

technique. Perform a 

one-handed technique by 

GENTLY pressing the orange 

Needle-Pro ® safety device 

against a table top or other 

hard, flat surface. AS THE ORANGE NEEDLE-PRO ® SAFETY DEVICE IS PRESSED, 

THE NEEDLE WILL FIRMLY ENGAGE INTO THE ORANGE NEEDLE-PRO ® SAFETY 

DEVICE. Visually confirm that the needle is fully engaged into the orange 

Needle-Pro ® safety device before discarding. Discard needle appropriately. Also 

discard the other (unused) needle provided in the dose pack. 

Upon suspension of the microspheres in the diluent, it is recommended to use 

RISPERDAL ® CONSTA ® immediately. If RISPERDAL ® CONSTA ® is not administered 

within 2 minutes of reconstitution, settling of the microspheres will occur and 

resuspension by shaking is necessary prior to administration. Keeping the vial 

upright, shake vigorously back and forth for as long as it takes to resuspend the 

microspheres. Once in suspension, the product may remain at room temperature 

(do not expose to temperatures above 77°F (25°C)). RISPERDAL ® CONSTA ® must 

be used within 6 hours of suspension. 

Parenteral drug products should be inspected visually for particulate matter and 

discoloration prior to administration, whenever solution and container permit. 

3 DOSAGE FORMS AND STRENGTHS 

RISPERDAL ® CONSTA ® is available in dosage strengths of 12.5 mg, 25 mg, 37.5 mg, 

and 50 mg risperidone. It is provided as a dose pack, consisting of a vial containing 

the risperidone microspheres, a pre-filled syringe containing 2 mL of diluent for 

RISPERDAL ® CONSTA ® , a SmartSite ® Needle-Free Vial Access Device, and two 

Needle-Pro ® safety needles for intramuscular injection (a 21 G UTW 1-inch needle 

with needle protection device for deltoid administration and a 20 G TW 2-inch 

needle with needle protection device for gluteal administration). 

4 CONTRAINDICATIONS 

RISPERDAL ® CONSTA ® (risperidone) is contraindicated in patients with a known 

hypersensitivity to the product. 

5 WARNINGS AND PRECAUTIONS 

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis 

Elderly patients with dementia-related psychosis treated with antipsychotic drugs 

are at an increased risk of death. RISPERDAL ® CONSTA ® (risperidone) is not 

approved for the treatment of dementia-related psychosis (see Boxed Warning). 

5.2 Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with 

Dementia-Related Psychosis 

Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including 

fatalities, were reported in patients (mean age 85 years; range 73-97) in trials of oral 

risperidone in elderly patients with dementia-related psychosis. In placebocontrolled 

trials, there was a significantly higher incidence of cerebrovascular 

adverse events in patients treated with oral risperidone compared to patients 

treated with placebo. RISPERDAL ® CONSTA ® is not approved for the treatment of 

patients with dementia-related psychosis [See also Boxed Warning and Warnings 

and Precautions (5.1)] 

5.3 Neuroleptic Malignant Syndrome (NMS) 

A potentially fatal symptom complex sometimes referred to as Neuroleptic 

Malignant Syndrome (NMS) has been reported in association with antipsychotic


drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered 

mental status, and evidence of autonomic instability (irregular pulse or blood 

pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may 

include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and 

acute renal failure. 

The diagnostic evaluation of patients with this syndrome is complicated. In arriving 

at a diagnosis, it is important to identify cases in which the clinical presentation 

includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and 

untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other 

important considerations in the differential diagnosis include central anticholinergic 

toxicity, heat stroke, drug fever, and primary central nervous system pathology. 

The management of NMS should include: (1) immediate discontinuation of 

antipsychotic drugs and other drugs not essential to concurrent therapy; (2) 

intensive symptomatic treatment and medical monitoring; and (3) treatment of any 

concomitant serious medical problems for which specific treatments are available. 

There is no general agreement about specific pharmacological treatment regimens 

for uncomplicated NMS. 

If a patient requires antipsychotic drug treatment after recovery from NMS, the 

potential reintroduction of drug therapy should be carefully considered. The patient 

should be carefully monitored, since recurrences of NMS have been reported. 

5.4 Tardive Dyskinesia 

A syndrome of potentially irreversible, involuntary, dyskinetic movements may 

develop in patients treated with antipsychotic drugs. Although the prevalence of 

the syndrome appears to be highest among the elderly, especially elderly women, 

it is impossible to rely upon prevalence estimates to predict, at the inception of 

antipsychotic treatment, which patients are likely to develop the syndrome. Whether 

antipsychotic drug products differ in their potential to cause tardive dyskinesia is 

unknown. 

The risk of developing tardive dyskinesia and the likelihood that it will become 

irreversible are believed to increase as the duration of treatment and the total 

cumulative dose of antipsychotic drugs administered to the patient increase. 

However, the syndrome can develop, although much less commonly, after relatively 

brief treatment periods at low doses. 

There is no known treatment for established cases of tardive dyskinesia, although 

the syndrome may remit, partially or completely, if antipsychotic treatment is 

withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially 

suppress) the signs and symptoms of the syndrome and thereby may possibly mask 

the underlying process. The effect that symptomatic suppression has upon the 

long-term course of the syndrome is unknown. 

Given these considerations, RISPERDAL ® CONSTA ® should be prescribed in a 

manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic 

antipsychotic treatment should generally be reserved for patients who suffer from 

a chronic illness that: (1) is known to respond to antipsychotic drugs, and (2) for 

whom alternative, equally effective, but potentially less harmful treatments are not 

available or appropriate. In patients who do require chronic treatment, the smallest 

dose and the shortest duration of treatment producing a satisfactory clinical 

response should be sought. The need for continued treatment should be reassessed 

periodically. 

If signs and symptoms of tardive dyskinesia appear in a patient treated with 

RISPERDAL ® CONSTA ® , drug discontinuation should be considered. However, some 

patients may require treatment with RISPERDAL ® CONSTA ® despite the presence 

of the syndrome. 

5.5 Hyperglycemia and Diabetes Mellitus 

Hyperglycemia, in some cases extreme and associated with ketoacidosis or 

hyperosmolar coma or death, has been reported in patients treated with atypical 

antipsychotics including RISPERDAL ® . Assessment of the relationship between 

atypical antipsychotic use and glucose abnormalities is complicated by the 

possibility of an increased background risk of diabetes mellitus in patients with 

schizophrenia and the increasing incidence of diabetes mellitus in the general 

population. Given these confounders, the relationship between atypical 

antipsychotic use and hyperglycemia-related adverse events is not completely 

understood. However, epidemiological studies suggest an increased risk of 

treatment-emergent hyperglycemia-related adverse events in patients treated with 

the atypical antipsychotics. Precise risk estimates for hyperglycemia-related 

adverse events in patients treated with atypical antipsychotics are not available. 

Patients with an established diagnosis of diabetes mellitus who are started on 

atypical antipsychotics should be monitored regularly for worsening of glucose 

control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history 

of diabetes) who are starting treatment with atypical antipsychotics should undergo 

fasting blood glucose testing at the beginning of treatment and periodically during 

treatment. Any patient treated with atypical antipsychotics should be monitored for 

symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and 

weakness. Patients who develop symptoms of hyperglycemia during treatment with 

atypical antipsychotics should undergo fasting blood glucose testing. In some 

cases, hyperglycemia has resolved when the atypical antipsychotic was 

discontinued; however, some patients required continuation of anti-diabetic 

treatment despite discontinuation of the suspect drug. 

5.6 Hyperprolactinemia 

As with other drugs that antagonize dopamine D2 receptors, risperidone elevates 

prolactin levels and the elevation persists during chronic administration. 

Risperidone is associated with higher levels of prolactin elevation than other 

antipsychotic agents. 

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced 

pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by 

impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, 

amenorrhea, gynecomastia, and impotence have been reported in patients 

receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when 

associated with hypogonadism may lead to decreased bone density in both female 

and male subjects. 

Tissue culture experiments indicate that approximately one-third of human breast 

cancers are prolactin dependent in vitro, a factor of potential importance if the 

prescription of these drugs is contemplated in a patient with previously detected 

breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet 

cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) 

was observed in the risperidone carcinogenicity studies conducted in mice and 

rats [see Nonclinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic 

studies conducted to date have shown an association between chronic 

administration of this class of drugs and tumorigenesis in humans; the available 

evidence is considered too limited to be conclusive at this time. 


RISPERDAL ® CONSTA ® may induce orthostatic hypotension associated with 

dizziness, tachycardia, and in some patients, syncope, especially during the initial 

dose-titration period with oral risperidone, probably reflecting its alpha-adrenergic 

antagonistic properties. Syncope was reported in 0.8% (12/1499 patients) of patients 

treated with RISPERDAL ® CONSTA ® in multiple-dose studies. Patients should be 

instructed in nonpharmacologic interventions that help to reduce the occurrence 

of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes 

before attempting to stand in the morning and slowly rising from a seated position). 

RISPERDAL ® CONSTA ® should be used with particular caution in (1) patients with 

known cardiovascular disease (history of myocardial infarction or ischemia, heart 

failure, or conduction abnormalities), cerebrovascular disease, and conditions 

which would predispose patients to hypotension, e.g., dehydration and 

hypovolemia, and (2) in the elderly and patients with renal or hepatic impairment. 

Monitoring of orthostatic vital signs should be considered in all such patients, and 

a dose reduction should be considered if hypotension occurs. Clinically significant 

hypotension has been observed with concomitant use of oral RISPERDAL ® and 

antihypertensive medication. 

5.8 Leukopenia, Neutropenia, and Agranulocytosis 

Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/ 

neutropenia have been reported temporally related to antipsychotic agents, 

including RISPERDAL ® CONSTA ® . Agranulocytosis has also been reported. 

Possible risk factors for leukopenia/neutropenia include pre-existing low white 

blood cell count (WBC) and a history of drug-induced leukopenia/neutropenia. 

Patients with a history of a clinically significant low WBC or a drug-induced 

leukopenia/neutropenia should have their complete blood count (CBC) monitored 

frequently during the first few months of therapy and discontinuation of 

RISPERDAL ® CONSTA ® should be considered at the first sign of a clinically 

significant decline in WBC in the absence of other causative factors. 

Patients with clinically significant neutropenia should be carefully monitored for 

fever or other symptoms or signs of infection and treated promptly if such symptoms 

or signs occur. Patients with severe neutropenia (absolute neutrophil count 


prescribing RISPERDAL ® CONSTA ® for patients who will be exposed to temperature 

extremes. 

5.15 Administration 

RISPERDAL ® CONSTA ® should be injected into the deltoid or gluteal muscle, and 

care must be taken to avoid inadvertent injection into a blood vessel. [See Dosage 

and Administration (2) and Adverse Reactions (6.8)] 

5.16 Antiemetic Effect 

Risperidone has an antiemetic effect in animals; this effect may also occur in 

humans, and may mask signs and symptoms of overdosage with certain drugs or 

of conditions such as intestinal obstruction, Reye’s syndrome, and brain tumor. 

5.17 Suicide 

There is an increased risk of suicide attempt in patients with schizophrenia or bipolar 

disorder, and close supervision of high-risk patients should accompany drug therapy. 

RISPERDAL ® CONSTA ® is to be administered by a health care professional [see 

Dosage and Administration (2)]; therefore, suicide due to an overdose is unlikely. 

5.18 Use in Patients with Concomitant Illness 

Clinical experience with RISPERDAL ® CONSTA ® in patients with certain concomitant 

systemic illnesses is limited. Patients with Parkinson’s Disease or Dementia with 

Lewy Bodies who receive antipsychotics, including RISPERDAL ® CONSTA ® , are 

reported to have an increased sensitivity to antipsychotic medications. 

Manifestations of this increased sensitivity have been reported to include confusion, 

obtundation, postural instability with frequent falls, extrapyramidal symptoms, and 

clinical features consistent with the neuroleptic malignant syndrome. 

Caution is advisable when using RISPERDAL ® CONSTA ® in patients with diseases 

or conditions that could affect metabolism or hemodynamic responses. 

RISPERDAL ® CONSTA ® has not been evaluated or used to any appreciable extent 

in patients with a recent history of myocardial infarction or unstable heart disease. 

Patients with these diagnoses were excluded from clinical studies during the 

product’s premarket testing. 

Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur 

in patients with severe renal impairment (creatinine clearance


experiencing adverse events, events were grouped in standardized categories 

using MedDRA terminology. 

Throughout this section, adverse reactions are reported. Adverse reactions are 

adverse events that were considered to be reasonably associated with the use of 

RISPERDAL ® CONSTA ® (adverse drug reactions) based on the comprehensive 

assessment of the available adverse event information. A causal association for 

RISPERDAL ® CONSTA ® often cannot be reliably established in individual cases. 

Further, because clinical trials are conducted under widely varying conditions, 

adverse reaction rates observed in the clinical trials of a drug cannot be directly 

compared to rates in the clinical trials of another drug and may not reflect the rates 

observed in clinical practice. 

The majority of all adverse reactions were mild to moderate in severity. 

6.1 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled 

Clinical Trials - Schizophrenia 

Table 1 lists the adverse reactions reported in 2% or more of RISPERDAL ® CONSTA ® - 

treated patients with schizophrenia in one 12-week double-blind, placebo-controlled 

trial. 

Table 1. Adverse Reactions in ≥ 2% of RISPERDAL ® CONSTA ® -Treated Patients 

with Schizophrenia in a 12-Week Double-Blind, Placebo-Controlled Trial 

Percentage of Patients Reporting Event 

RISPERDAL ® CONSTA ® Placebo 

System/Organ Class 25 mg 50 mg 

Adverse Reaction (N=99) (N=103) (N=98) 

Eye disorders 

Vision blurred 2 3 0 

Gastrointestinal disorders 

Constipation 5 7 1 

Dry mouth 0 7 1 

Dyspepsia 6 6 0 

Nausea 3 4 5 

Toothache 1 3 0 

Salivary hypersecretion 4 1 0 

General disorders and administration 

site conditions 

Fatigue* 3 9 0 

Edema peripheral 2 3 1 

Pain 4 1 0 

Pyrexia 2 1 0 

Infections and infestations 

Upper respiratory tract infection 2 0 1 

Investigations 

Weight increased 5 4 2 

Weight decreased 4 1 1 

Musculoskeletal and connective 

tissue disorders 

Pain in extremity 6 2 1 

Nervous system disorders 

Headache 15 21 12 

Parkinsonism* 8 15 9 

Dizziness 7 11 6 

Akathisia* 4 11 6 

Sedation* 5 6 3 

Tremor 0 3 0 

Syncope 2 1 0 

Hypoesthesia 2 0 0 

Respiratory, thoracic and 

mediastinal disorders 

Cough 4 2 3 

Sinus congestion 2 0 0 

Skin and subcutaneous tissue disorders 

Acne 2 2 0 

Dry skin 2 0 0 

* Fatigue includes fatigue and asthenia. Parkinsonism includes extrapyramidal 

disorder, musculoskeletal stiffness, muscle rigidity, and bradykinesia. Akathisia 

includes akathisia and restlessness. Sedation includes sedation and somnolence. 

6.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled 

Clinical Trials – Bipolar Disorder 

Table 2 lists the treatment-emergent adverse reactions reported in 2% or more of 

RISPERDAL ® CONSTA ® -treated patients in the 24-month double-blind, placebocontrolled 

treatment period of the trial assessing the efficacy and safety of 

RISPERDAL ® CONSTA ® when administered as monotherapy for maintenance 

treatment in patients with Bipolar I Disorder. 

Table 2. Adverse Reactions in ≥2% of Patients with Bipolar I Disorder Treated 

with RISPERDAL ® CONSTA ® as Monotherapy in a 24-Month Double-Blind, 

Placebo-Controlled Trial 


System/Organ Class RISPERDAL ® CONSTA ® Placebo 

Adverse Reaction (N=154) (N=149) 


Weight increased 5 1 


Dizziness 3 1 

Vascular disorders 

Hypertension 3 1 

Table 3 lists the treatment-emergent adverse reactions reported in 4% or more of 

patients in the 52-week double-blind, placebo-controlled treatment phase of a trial 

assessing the efficacy and safety of RISPERDAL ® CONSTA ® when administered as 

adjunctive maintenance treatment in patients with bipolar disorder. 

Table 3. Adverse Reactions in ≥ 4% of Patients with Bipolar Disorder Treated 

with RISPERDAL ® CONSTA ® as Adjunctive Therapy in a 52-Week Double-Blind, 

Placebo-Controlled Trial 


RISPERDAL ® CONSTA ® + Placebo + 

System/Organ Class Treatment as Usuala Treatment as Usuala Adverse Reaction (N=72) (N=67) 

General disorders and administration 

site conditions 

Gait abnormal 4 0 

Infections and infestations 

Upper respiratory tract infection 6 3 


Weight increased 7 1 

Metabolism and nutrition disorders 

Decreased appetite 6 1 

Increased appetite 4 0 

Musculoskeletal and connective 

tissue disorders 

Arthralgia 4 3 


Tremor 24 16 

Parkinsonismb 15 6 

Dyskinesiab 6 3 

Sedationc 7 1 

Disturbance in attention 4 0 

Reproductive system and breast disorders 

Amenorrhea 4 1 

Respiratory, thoracic and 

mediastinal disorders 

Cough 4 1 

a Patients received double-blind RISPERDAL ® CONSTA ® or placebo in addition to 

continuing their treatment as usual, which included mood stabilizers, 

antidepressants, and/or anxiolytics. 

b Parkinsonism includes muscle rigidity, hypokinesia, cogwheel rigidity, and 

bradykinesia. Dyskinesia includes muscle twitching and dyskinesia. 

c Sedation includes sedation and somnolence. 

6.3 Other Adverse Reactions Observed During the Premarketing Evaluation of 

RISPERDAL ® CONSTA ® 

The following additional adverse reactions occurred in < 2% of the 

RISPERDAL ® CONSTA ® -treated patients in the above schizophrenia double-blind, 

placebo-controlled trial dataset, in < 2% of the RISPERDAL ® CONSTA ® -treated 

patients in the above double-blind, placebo-controlled period of the monotherapy 

bipolar disorder trial dataset, or in < 4% of the RISPERDAL ® CONSTA ® -treated 

patients in the above double-blind, placebo-controlled period of the adjunctive 

treatment bipolar disorder trial dataset. The following also includes additional 

adverse reactions reported at any frequency in RISPERDAL ® CONSTA ® -treated 

patients who participated in the open-label phases of the above bipolar disorder 

studies and in other studies, including double-blind, active controlled and 

open-label studies in schizophrenia and bipolar disorder. 

Blood and lymphatic system disorders: anemia, neutropenia 

Cardiac disorders: tachycardia, atrioventricular block first degree, palpitations, 

sinus bradycardia, bundle branch block left, bradycardia, sinus tachycardia, bundle 

branch block right 

Ear and labyrinth disorders: ear pain, vertigo 

Endocrine disorders: hyperprolactinemia 

Eye disorders: conjunctivitis, visual acuity reduced 

Gastrointestinal disorders: diarrhea, vomiting, abdominal pain upper, abdominal 

pain, stomach discomfort, gastritis


General disorders and administration site conditions: injection site pain, chest 

discomfort, chest pain, influenza like illness, sluggishness, malaise, induration, 

injection site induration, injection site swelling, injection site reaction, face edema 

Immune system disorders: hypersensitivity 

Infections and infestations: nasopharyngitis, influenza, bronchitis, urinary tract 

infection, rhinitis, respiratory tract infection, ear infection, pneumonia, lower 

respiratory tract infection, pharyngitis, sinusitis, viral infection, infection, localized 

infection, cystitis, gastroenteritis, subcutaneous abscess 

Injury and poisoning: fall, procedural pain 

Investigations: blood prolactin increased, alanine aminotransferase increased, 

electrocardiogram abnormal, gamma-glutamyl transferase increased, blood 

glucose increased, hepatic enzyme increased, aspartate aminotransferase 

increased, electrocardiogram QT prolonged, glucose urine present 

Metabolism and nutritional disorders: anorexia, hyperglycemia 

Musculoskeletal, connective tissue and bone disorders: posture abnormal, myalgia, 

back pain, buttock pain, muscular weakness, neck pain, musculoskeletal chest pain 

Nervous system disorders: coordination abnormal, dystonia, tardive dyskinesia, 

drooling, paresthesia, dizziness postural, convulsion, akinesia, hypokinesia, 

dysarthria 

Psychiatric disorders: insomnia, agitation, anxiety, sleep disorder, depression, initial 

insomnia, libido decreased, nervousness 

Renal and urinary disorders: urinary incontinence 

Reproductive system and breast disorders: galactorrhea, oligomenorrhea, erectile 

dysfunction, sexual dysfunction, ejaculation disorder, gynecomastia, breast 

discomfort, menstruation irregular, menstruation delayed, menstrual disorder, 

ejaculation delayed 

Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal 

pain, dyspnea, rhinorrhea 

Skin and subcutaneous tissue disorders: rash, eczema, pruritus generalized, 

pruritus 

Vascular disorders: hypotension, orthostatic hypotension 

6.4 Discontinuations Due to Adverse Reactions 

Schizophrenia 

Approximately 11% (22/202) of RISPERDAL ® CONSTA ® -treated patients in the 

12-week double-blind, placebo-controlled schizophrenia trial discontinued 

treatment due to an adverse event, compared with 13% (13/98) who received 

placebo. The adverse reactions associated with discontinuation in two or more 

RISPERDAL ® CONSTA ® -treated patients were: agitation (3%), depression (2%), 

anxiety (1%), and akathisia (1%). 

Bipolar Disorder 

In the 24-month double-blind, placebo-controlled treatment period of the trial 


monotherapy for maintenance treatment in patients with bipolar I disorder, 1 (0.6%) 

of 154 RISPERDAL ® CONSTA ® -treated patients discontinued due to an adverse 

reaction (hyperglycemia). 

In the 52-week double-blind phase of the placebo-controlled trial in which 

RISPERDAL ® CONSTA ® was administered as adjunctive therapy to patients with 

bipolar disorder in addition to continuing with their treatment as usual, approximately 

4% (3/72) of RISPERDAL ® CONSTA ® -treated patients discontinued treatment due to 

an adverse event, compared with 1.5% (1/67) of placebo-treated patients. Adverse 

reactions associated with discontinuation in RISPERDAL ® CONSTA ® -treated 

patients were: hypokinesia (one patient) and tardive dyskinesia (one patient). 

6.5 Dose Dependency of Adverse Reactions in Clinical Trials 

Extrapyramidal Symptoms: 

Two methods were used to measure extrapyramidal symptoms (EPS) in the 12-week 

double-blind, placebo-controlled trial comparing three doses of RISPERDAL ® CONSTA ® 

(25 mg, 50 mg, and 75 mg) with placebo in patients with schizophrenia, including: (1) the 

incidence of spontaneous reports of EPS symptoms; and (2) the change from baseline 

to endpoint on the total score (sum of the subscale scores for parkinsonism, dystonia, 

and dyskinesia) of the Extrapyramidal Symptom Rating Scale (ESRS). 

As shown in Table 1, the overall incidence of EPS-related adverse reactions 

(akathisia, dystonia, parkinsonism, and tremor) in patients treated with 25 mg 

RISPERDAL ® CONSTA ® was comparable to that of patients treated with placebo; 

the incidence of EPS-related adverse reactions was higher in patients treated with 

50 mg RISPERDAL ® CONSTA ® . 

The median change from baseline to endpoint in total ESRS score showed no 

worsening in patients treated with RISPERDAL ® CONSTA ® compared with patients 

treated with placebo: 0 (placebo group); -1 (25-mg group, significantly less than the 

placebo group); and 0 (50-mg group). 

Dystonia 

Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle 

groups, may occur in susceptible individuals during the first few days of treatment. 

Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to 

tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of 

the tongue. While these symptoms can occur at low doses, they occur more frequently 

and with greater severity with high potency and at higher doses of first generation 

antipsychotic drugs. An elevated risk of acute dystonia is observed in males and 

younger age groups. 

6.6 Changes in Body Weight 

In the 12-week double-blind, placebo-controlled trial in patients with schizophrenia, 

9% of patients treated with RISPERDAL ® CONSTA ® , compared with 6% of patients 

treated with placebo, experienced a weight gain of >7% of body weight at endpoint. 

In the 24-month double-blind, placebo-controlled treatment period of a trial 


monotherapy for maintenance treatment in patients with bipolar I disorder, 11.6% 

of patients treated with RISPERDAL ® CONSTA ® compared with 2.8% of patients 

treated with placebo experienced a weight gain of >7% of body weight at endpoint. 

In the 52-week double-blind, placebo-controlled trial in patients with bipolar disorder, 

26.8% of patients treated with RISPERDAL ® CONSTA ® as adjunctive treatment in 

addition to continuing their treatment as usual, compared with 27.3% of patients 

treated with placebo in addition to continuing their treatment as usual, experienced 

a weight gain of >7% of body weight at endpoint. 

6.7 Changes in ECG 

The electrocardiograms of 202 schizophrenic patients treated with 25 mg or 50 mg 

RISPERDAL ® CONSTA ® and 98 schizophrenic patients treated with placebo in the 

12-week double-blind, placebo-controlled trial were evaluated. Compared with placebo, 

there were no statistically significant differences in QTc intervals (using Fridericia’s and 

linear correction factors) during treatment with RISPERDAL ® CONSTA ® . 

The electrocardiograms of 227 patients with Bipolar I Disorder were evaluated in 

the 24-month double-blind, placebo-controlled period. There were no clinically 

relevant differences in QTc intervals (using Fridericia’s and linear correction factors) 

during treatment with RISPERDAL ® CONSTA ® compared to placebo. 

The electrocardiograms of 85 patients with bipolar disorder were evaluated in the 

52-week double-blind, placebo-controlled trial. There were no statistically 

significant differences in QTc intervals (using Fridericia’s and linear correction 

factors) during treatment with RISPERDAL ® CONSTA ® 25 mg, 37.5 mg, or 50 mg 

when administered as adjunctive treatment in addition to continuing treatment as 

usual compared to placebo. 

6.8 Pain Assessment and Local Injection Site Reactions 

The mean intensity of injection pain reported by patients with schizophrenia using a 

visual analog scale (0 = no pain to 100 = unbearably painful) decreased in all 

treatment groups from the first to the last injection (placebo: 16.7 to 12.6; 25 mg: 12.0 

to 9.0; 50 mg: 18.2 to 11.8). After the sixth injection (Week 10), investigator ratings 

indicated that 1% of patients treated with 25 mg or 50 mg RISPERDAL ® CONSTA ® 

experienced redness, swelling, or induration at the injection site. 

In a separate study to observe local-site tolerability in which RISPERDAL ® CONSTA ® 

was administered into the deltoid muscle every 2 weeks over a period of 8 weeks, 

no patient discontinued treatment due to local injection site pain or reaction. 

Clinician ratings indicated that only mild redness, swelling, or induration at the 

injection site was observed in subjects treated with 37.5 mg or 50 mg 

RISPERDAL ® CONSTA ® at 2 hours after deltoid injection. All ratings returned to 

baseline at the predose assessment of the next injection 2 weeks later. No moderate 

or severe reactions were observed in any subject. 

6.9 Postmarketing Experience 

The following adverse reactions have been identified during postapproval use of 

risperidone; because these reactions are reported voluntarily from a population of 

uncertain size, it is not possible to reliably estimate their frequency: agranulocytosis, 

alopecia, anaphylactic reaction, angioedema, atrial fibrillation, diabetes mellitus, 

diabetic ketoacidosis in patients with impaired glucose metabolism, hypoglycemia, 

hypothermia, inappropriate antidiuretic hormone secretion, intestinal obstruction, 

jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apnea syndrome, 

thrombocytopenia, urinary retention, and water intoxication. In addition, the 

following adverse reactions have been observed during post approval use of 

RISPERDAL ® CONSTA ® : cerebrovascular disorders, including cerebrovascular 

accidents, and diabetes mellitus aggravated. 

Retinal artery occlusion after injection of RISPERDAL ® CONSTA ® has been reported 

during postmarketing surveillance. This has been reported in the presence of 

abnormal arteriovenous anastomosis. 

Serious injection site reactions including abscess, cellulitis, cyst, hematoma, 

necrosis, nodule, and ulcer have been reported with RISPERDAL ® CONSTA ® 

during postmarketing surveillance. Isolated cases required surgical intervention. 

7 DRUG INTERACTIONS 

The interactions of RISPERDAL ® CONSTA ® with coadministration of other drugs 

have not been systematically evaluated. The drug interaction data provided in this 

section is based on studies with oral RISPERDAL ® . 

7.1 Centrally-Acting Drugs and Alcohol 

Given the primary CNS effects of risperidone, caution should be used when 

RISPERDAL ® CONSTA ® is administered in combination with other centrally-acting 

drugs or alcohol. 

7.2 Drugs with Hypotensive Effects 

Because of its potential for inducing hypotension, RISPERDAL ® CONSTA ® may enhance 

the hypotensive effects of other therapeutic agents with this potential. 

7.3 Levodopa and Dopamine Agonists 

RISPERDAL ® CONSTA ® may antagonize the effects of levodopa and dopamine 

agonists.


7.4 Amitriptyline 

Amitriptyline did not affect the pharmacokinetics of risperidone or of risperidone 

and 9-hydroxyrisperidone combined following concomitant administration with oral 

RISPERDAL ® . 

7.5 Cimetidine and Ranitidine 

Cimetidine and ranitidine increased the bioavailability of oral risperidone by 64% 

and 26%, respectively. However, cimetidine did not affect the AUC of risperidone 

and 9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of 

risperidone and 9-hydroxyrisperidone combined by 20%. 

7.6 Clozapine 

Chronic administration of clozapine with risperidone may decrease the clearance 

of risperidone. 

7.7 Lithium 

Repeated doses of oral RISPERDAL ® (3 mg twice daily) did not affect the exposure 

(AUC) or peak plasma concentrations (Cmax) of lithium (n=13). 

7.8 Valproate 

Repeated doses of oral RISPERDAL ® (4 mg once daily) did not affect the pre-dose 

or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day 

in three divided doses) compared to placebo (n=21). However, there was a 

20% increase in valproate peak plasma concentration (Cmax) after concomitant 

administration of oral RISPERDAL ® . 

7.9 Digoxin 

Oral RISPERDAL ® (0.25 mg twice daily) did not show a clinically relevant effect on 

the pharmacokinetics of digoxin. 

7.10 Topiramate 

Oral RISPERDAL ® administered at doses from 1-6 mg/day concomitantly with 

topiramate 400 mg/day resulted in a 23% decrease in risperidone Cmax and a 33% 

decrease in risperidone AUC0-12 hour at steady state. Minimal reductions in the 

exposure to risperidone and 9-hydroxyrisperidone combined, and no change for 

9-hydroxyrisperidone were observed. This interaction is unlikely to be of clinical 

significance. There was no clinically relevant effect of oral RISPERDAL ® on the 

pharmacokinetics of topiramate. 

7.11 Drugs That Inhibit CYP 2D6 and Other CYP Isozymes 

Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is 

polymorphic in the population and that can be inhibited by a variety of psychotropic 

and other drugs [see Clinical Pharmacology (12.3)]. Drug interactions that reduce 

the metabolism of risperidone to 9-hydroxyrisperidone would increase the plasma 

concentrations of risperidone and lower the concentrations of 9-hydroxyrisperidone. 

Analysis of clinical studies involving a modest number of poor metabolizers 

(n=˜ 70 patients) does not suggest that poor and extensive metabolizers have different 

rates of adverse effects. No comparison of effectiveness in the two groups has 

been made. 

In vitro studies showed that drugs metabolized by other CYP isozymes, including 

1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism. 

Fluoxetine and Paroxetine 

Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily), CYP 2D6 inhibitors, 

have been shown to increase the plasma concentration of risperidone 2.5-2.8 fold 

and 3-9 fold respectively. Fluoxetine did not affect the plasma concentration of 

9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone 

by about 10%. When either concomitant fluoxetine or paroxetine is initiated or 

discontinued, the physician should re-evaluate the dose of RISPERDAL ® CONSTA ® . 

When initiation of fluoxetine or paroxetine is considered, patients may be placed 

on a lower dose of RISPERDAL ® CONSTA ® between 2 to 4 weeks before the planned 

start of fluoxetine or paroxetine therapy to adjust for the expected increase in 

plasma concentrations of risperidone. When fluoxetine or paroxetine is initiated in 

patients receiving the recommended dose of 25 mg RISPERDAL ® CONSTA ® , it is 

recommended to continue treatment with the 25-mg dose unless clinical judgment 

necessitates lowering the RISPERDAL ® CONSTA ® dose to 12.5 mg or necessitates 

interruption of RISPERDAL ® CONSTA ® treatment. When RISPERDAL ® CONSTA ® is 

initiated in patients already receiving fluoxetine or paroxetine, a starting dose of 

12.5 mg can be considered. The efficacy of the 12.5 mg dose has not been 

investigated in clinical trials. [See also DOSAGE AND ADMINISTRATION (2.5)]. The 

effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the 

pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied. 

Erythromycin 

There were no significant interactions between oral RISPERDAL ® and erythromycin. 

7.12 Carbamazepine and Other CYP 3A4 Enzyme Inducers 

Carbamazepine co-administration with oral RISPERDAL ® decreased the steadystate 

plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%. 

Plasma concentrations of carbamazepine did not appear to be affected. 

Co-administration of other known CYP 3A4 enzyme inducers (e.g., phenytoin, 

rifampin, and phenobarbital) with risperidone may cause similar decreases in the 

combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which 

could lead to decreased efficacy of RISPERDAL ® CONSTA ® treatment. At the 

initiation of therapy with carbamazepine or other known hepatic enzyme inducers, 

patients should be closely monitored during the first 4–8 weeks, since the dose of 

RISPERDAL ® CONSTA ® may need to be adjusted. A dose increase, or additional 

oral RISPERDAL ® , may need to be considered. On discontinuation of carbamazepine 

or other CYP 3A4 hepatic enzyme inducers, the dosage of RISPERDAL ® CONSTA ® 

should be re-evaluated and, if necessary, decreased. Patients may be placed on 

a lower dose of RISPERDAL ® CONSTA ® between 2 to 4 weeks before the 

planned discontinuation of carbamazepine or other CYP 3A4 enzyme inducers to 

adjust for the expected increase in plasma concentrations of risperidone plus 

9-hydroxyrisperidone. For patients treated with the recommended dose of 25 mg 

RISPERDAL ® CONSTA ® and discontinuing from carbamazepine or other CYP 3A4 

enzyme inducers, it is recommended to continue treatment with the 25-mg dose 

unless clinical judgment necessitates lowering the RISPERDAL ® CONSTA ® dose to 

12.5 mg or necessitates interruption of RISPERDAL ® CONSTA ® treatment. The 

efficacy of the 12.5 mg dose has not been investigated in clinical trials. [See also 

DOSAGE AND ADMINSTRATION (2.5)] 

7.13 Drugs Metabolized by CYP 2D6 

In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. 

Therefore, RISPERDAL ® CONSTA ® is not expected to substantially inhibit 

the clearance of drugs that are metabolized by this enzymatic pathway. In 

drug interaction studies, oral RISPERDAL ® did not significantly affect the 

pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6. 

8 USE IN SPECIFIC POPULATIONS 

8.1 Pregnancy 

Pregnancy Category C. 

The teratogenic potential of oral risperidone was studied in three embryofetal 

development studies in Sprague-Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 

6 times the oral maximum recommended human dose [MRHD] on a mg/m2 basis) 

and in one embryofetal development study in New Zealand rabbits (0.31-5 mg/kg or 

0.4 to 6 times the oral MRHD on a mg/m2 basis). The incidence of malformations 

was not increased compared to control in offspring of rats or rabbits given 0.4 to 

6 times the oral MRHD on a mg/m2 basis. In three reproductive studies in rats (two 

peri/post-natal development studies and a multigenerational study), there was an 

increase in pup deaths during the first 4 days of lactation at doses of 0.16-5 mg/kg 

or 0.1 to 3 times the oral MRHD on a mg/m2 basis. It is not known whether these 

deaths were due to a direct effect on the fetuses or pups or to effects on the dams. 

There was no no-effect dose for increased rat pup mortality. In one peri/post-natal 

development study, there was an increase in stillborn rat pups at a dose of 2.5 mg/kg 

or 1.5 times the oral MRHD on a mg/m2 basis. In a cross-fostering study in Wistar 

rats, toxic effects on the fetus or pups, as evidenced by a decrease in the number 

of live pups and an increase in the number of dead pups at birth (Day 0), and a 

decrease in birth weight in pups of drug-treated dams were observed. In addition, 

there was an increase in deaths by Day 1 among pups of drug-treated dams, 

regardless of whether or not the pups were cross-fostered. Risperidone also 

appeared to impair maternal behavior in that pup body weight gain and survival (from 

Days 1 to 4 of lactation) were reduced in pups born to control but reared by 

drug-treated dams. These effects were all noted at the one dose of risperidone 

tested, i.e., 5 mg/kg or 3 times the oral MRHD on a mg/m2 basis. 

No studies were conducted with RISPERDAL ® CONSTA ® . 

Placental transfer of risperidone occurs in rat pups. There are no adequate and 

well-controlled studies in pregnant women. However, there was one report of a case 

of agenesis of the corpus callosum in an infant exposed to risperidone in utero. The 

causal relationship to oral RISPERDAL ® therapy is unknown. Reversible extrapyramidal 

symptoms in the neonate were observed following postmarketing use of risperidone 

during the last trimester of pregnancy. 

RISPERDAL ® CONSTA ® should be used during pregnancy only if the potential 

benefit justifies the potential risk to the fetus. 

8.2 Labor and Delivery 

The effect of RISPERDAL ® CONSTA ® on labor and delivery in humans is unknown. 

8.3 Nursing Mothers 

Risperidone and 9-hydroxyrisperidone are also excreted in human breast milk. 

Therefore, women should not breast-feed during treatment with RISPERDAL ® CONSTA ® 

and for at least 12 weeks after the last injection. 

8.4 Pediatric Use 

RISPERDAL ® CONSTA ® has not been studied in children younger than 18 years old. 

8.5 Geriatric Use 

In an open-label study, 57 clinically stable, elderly patients (≥ 65 years old) with 

schizophrenia or schizoaffective disorder received RISPERDAL ® CONSTA ® every 

2 weeks for up to 12 months. In general, no differences in the tolerability of 

RISPERDAL ® CONSTA ® were observed between otherwise healthy elderly and 

nonelderly patients. Therefore, dosing recommendations for otherwise healthy 

elderly patients are the same as for nonelderly patients. Because elderly patients 

exhibit a greater tendency to orthostatic hypotension than nonelderly patients, 

elderly patients should be instructed in nonpharmacologic interventions that help 

to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the 

bed for several minutes before attempting to stand in the morning and slowly rising 

from a seated position). In addition, monitoring of orthostatic vital signs should be 

considered in elderly patients for whom orthostatic hypotension is of concern [see 

Warnings and Precautions (5.7)].


Concomitant use with Furosemide in Elderly Patients with Dementia-Related 

Psychosis 

In two of four placebo-controlled trials in elderly patients with dementia-related 

psychosis, a higher incidence of mortality was observed in patients treated with 

furosemide plus oral risperidone when compared to patients treated with oral 

risperidone alone or with oral placebo plus furosemide. No pathological mechanism 

has been identified to explain this finding, and no consistent pattern for cause 

of death was observed. An increase of mortality in elderly patients with 

dementia-related psychosis was seen with the use of oral risperidone regardless 

of concomitant use with furosemide. RISPERDAL ® CONSTA ® is not approved for 

the treatment of patients with dementia-related psychosis. [See Boxed Warning 

and Warnings and Precautions (5.1)] 

9 DRUG ABUSE AND DEPENDENCE 

9.1 Controlled Substance 

RISPERDAL ® CONSTA ® (risperidone) is not a controlled substance. 

9.2 Abuse 

RISPERDAL ® CONSTA ® has not been systematically studied in animals or humans 

for its potential for abuse. Because RISPERDAL ® CONSTA ® is to be administered 

by health care professionals, the potential for misuse or abuse by patients is low. 

9.3 Dependence 

RISPERDAL ® CONSTA ® has not been systematically studied in animals or humans 

for its potential for tolerance or physical dependence. 

10 OVERDOSAGE 

10.1 Human Experience 

No cases of overdose were reported in premarketing studies with 

RISPERDAL ® CONSTA ® . Because RISPERDAL ® CONSTA ® is to be administered by 

health care professionals, the potential for overdosage by patients is low. 

In premarketing experience with oral RISPERDAL ® , there were eight reports of 

acute RISPERDAL ® overdosage, with estimated doses ranging from 20 to 300 mg 

and no fatalities. In general, reported signs and symptoms were those resulting 

from an exaggeration of the drug’s known pharmacological effects, i.e., drowsiness 

and sedation, tachycardia and hypotension, and extrapyramidal symptoms. One 

case, involving an estimated overdose of 240 mg, was associated with hyponatremia, 

hypokalemia, prolonged QT, and widened QRS. Another case, involving an estimated 

overdose of 36 mg, was associated with a seizure. 

Postmarketing experience with oral RISPERDAL ® includes reports of acute 

overdose, with estimated doses of up to 360 mg. In general, the most frequently 

reported signs and symptoms are those resulting from an exaggeration of the 

drug’s known pharmacological effects, i.e., drowsiness, sedation, tachycardia, 

hypotension, and extrapyramidal symptoms. Other adverse reactions reported since 

market introduction related to oral RISPERDAL ® overdose include prolonged QT 

interval and convulsions. Torsade de pointes has been reported in association with 

combined overdose of oral RISPERDAL ® and paroxetine. 

10.2 Management of Overdosage 

In case of acute overdosage, establish and maintain an airway and ensure adequate 

oxygenation and ventilation. Cardiovascular monitoring should commence immediately 

and should include continuous electrocardiographic monitoring to detect possible 

arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, 

and quinidine carry a theoretical hazard of QT prolonging effects that might be additive 

to those of risperidone. Similarly, it is reasonable to expect that the alpha-blocking 

properties of bretylium might be additive to those of risperidone, resulting in 

problematic hypotension. 

There is no specific antidote to risperidone. Therefore, appropriate supportive 

measures should be instituted. The possibility of multiple drug involvement should 

be considered. Hypotension and circulatory collapse should be treated with 

appropriate measures, such as intravenous fluids and/or sympathomimetic agents 

(epinephrine and dopamine should not be used, since beta stimulation may worsen 

hypotension in the setting of risperidone-induced alpha blockade). In cases of 

severe extrapyramidal symptoms, anticholinergic medication should be 

administered. Close medical supervision and monitoring should continue until the 

patient recovers. 

11 DESCRIPTION 

Risperidone is a psychotropic agent belonging to the chemical class of 

benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro- 

1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2a]pyrimidin-4-one. 

Its molecular formula is C23H27FN4O2 and its molecular weight is 

410.49. The structural formula is: 

Risperidone is practically insoluble in water, freely soluble in methylene chloride, and 

soluble in methanol and 0.1 N HCl. 

RISPERDAL ® CONSTA ® (risperidone) Long-Acting Injection is a combination of 

extended-release microspheres for injection and diluent for parenteral use. 

The extended-release microspheres formulation is a white to off-white, free-flowing 

powder that is available in dosage strengths of 12.5 mg, 25 mg, 37.5 mg, or 50 mg 

risperidone per vial. Risperidone is micro-encapsulated in 7525 polylactideco-glycolide 

(PLG) at a concentration of 381 mg risperidone per gram of microspheres. 

The diluent for parenteral use is a clear, colorless solution. Composition of the 

diluent includes polysorbate 20, sodium carboxymethyl cellulose, disodium 

hydrogen phosphate dihydrate, citric acid anhydrous, sodium chloride, sodium 

hydroxide, and water for injection. The microspheres are suspended in the diluent 

prior to injection. 

RISPERDAL ® CONSTA ® is provided as a dose pack, consisting of a vial containing 

the microspheres, a pre-filled syringe containing the diluent, a SmartSite ® 

Needle-Free Vial Access Device, and two Needle-Pro ® safety needles (a 21 G UTW 

1-inch needle with needle protection device for deltoid administration and a 20 G TW 

2-inch needle with needle protection device for gluteal administration). 

12 CLINICAL PHARMACOLOGY 

12.1 Mechanism of Action 

The mechanism of action of RISPERDAL ® CONSTA ® , as with other drugs used to 

treat schizophrenia, is unknown. However, it has been proposed that the drug’s 

therapeutic activity in schizophrenia is mediated through a combination of dopamine 

Type 2 (D2) and serotonin Type 2 (5HT2) receptor antagonism. 

RISPERDAL ® is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 

7.3 nM) for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, 

and H1 histaminergic receptors. RISPERDAL ® acts as an antagonist at other receptors, 

but with lower potency. RISPERDAL ® has low to moderate affinity (Ki of 47 to 253 nM) 

for the serotonin 5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 

800 nM) for the dopamine D1 and haloperidol-sensitive sigma site, and no affinity 

(when tested at concentrations >10-5 M) for cholinergic muscarinic or β1 and β2 

adrenergic receptors. 

12.2 Pharmacodynamics 

The clinical effect from RISPERDAL ® CONSTA ® results from the combined 

concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone 

[see Clinical Pharmacology (12.3)]. Antagonism at receptors other than D2 and 5HT2 [see Clinical Pharmacology (12.1)] may explain some of the other effects of 


12.3 Pharmacokinetics 

Absorption 

After a single intramuscular (gluteal) injection of RISPERDAL ® CONSTA ® , there is 

a small initial release of the drug (< 1% of the dose), followed by a lag time of 3 

weeks. The main release of the drug starts from 3 weeks onward, is maintained 

from 4 to 6 weeks, and subsides by 7 weeks following the intramuscular (IM) 

injection. Therefore, oral antipsychotic supplementation should be given during the 

first 3 weeks of treatment with RISPERDAL ® CONSTA ® to maintain therapeutic 

levels until the main release of risperidone from the injection site has begun [see 

Dosage and Administration (2)]. Following single doses of RISPERDAL ® CONSTA ® , 

the pharmacokinetics of risperidone, 9-hydroxyrisperidone (the major metabolite), 

and risperidone plus 9-hydroxy risperidone were linear in the dosing range of 

12.5 mg to 50 mg. 

The combination of the release profile and the dosage regimen (IM injections every 

2 weeks) of RISPERDAL ® CONSTA ® results in sustained therapeutic concentrations. 

Steady-state plasma concentrations are reached after 4 injections and are 

maintained for 4 to 6 weeks after the last injection. Following multiple doses of 25 mg 

and 50 mg RISPERDAL ® CONSTA ® , plasma concentrations of risperidone, 

9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone were linear. 

Deltoid and gluteal intramuscular injections at the same doses are bioequivalent 

and, therefore, interchangeable. 

Distribution 

Once absorbed, risperidone is rapidly distributed. The volume of distribution is 

1-2 L/kg. In plasma, risperidone is bound to albumin and α1-acid glycoprotein. The 

plasma protein binding of risperidone is approximately 90%, and that of its major 

metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone 

displaces each other from plasma binding sites. High therapeutic concentrations 

of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine (10 mcg/mL) 

caused only a slight increase in the free fraction of risperidone at 10 ng/mL and of 

9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance. 

Metabolism and Drug Interactions 

Risperidone is extensively metabolized in the liver. The main metabolic pathway is 

through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 

2D6. A minor metabolic pathway is through N-dealkylation. The main metabolite, 

9-hydroxyrisperidone, has similar pharmacological activity as risperidone. 

Consequently, the clinical effect of the drug results from the combined concentrations 

of risperidone plus 9-hydroxyrisperidone. 

CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for 

metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other 

drugs. CYP 2D6 is subject to genetic polymorphism (about 6%-8% of Caucasians, 

and a very low percentage of Asians, have little or no activity and are “poor 

metabolizers”) and to inhibition by a variety of substrates and some non-substrates, 

notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone rapidly into 

9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more


slowly. Although extensive metabolizers have lower risperidone and higher 

9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics 

of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, 

are similar in extensive and poor metabolizers. 

The interactions of RISPERDAL ® CONSTA ® with coadministration of other drugs 

have not been systematically evaluated in human subjects. Drug interactions are 

based primarily on experience with oral RISPERDAL ® . Risperidone could be subject 

to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6 interfere with 

conversion of risperidone to 9-hydroxyrisperidone [see Drug Interactions (7.11)]. 

This occurs with quinidine, giving essentially all recipients a risperidone 

pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits and 

adverse effects of RISPERDAL ® in patients receiving quinidine have not been 

evaluated, but observations in a modest number (n=˜70) of poor metabolizers given 

oral RISPERDAL ® do not suggest important differences between poor and extensive 

metabolizers. Second, co-administration of carbamazepine and other known 

enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with oral 

RISPERDAL ® cause a decrease in the combined plasma concentrations of 

risperidone and 9-hydroxyrisperidone [see Drug Interactions (7.12)]. It would also 

be possible for risperidone to interfere with metabolism of other drugs metabolized 

by CYP 2D6. Relatively weak binding of risperidone to the enzyme suggests this is 

unlikely [see Drug Interactions (7.11)]. 

Excretion 

Risperidone and its metabolites are eliminated via the urine and, to a much lesser 

extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral 

dose of 14C-risperidone administered as solution to three healthy male volunteers, 

total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 

14% in the feces. 

The apparent half-life of risperidone plus 9-hydroxyrisperidone following 

RISPERDAL ® CONSTA ® administration is 3 to 6 days, and is associated with a 

monoexponential decline in plasma concentrations. This half-life of 3-6 days is related 

to the erosion of the microspheres and subsequent absorption of risperidone. The 

clearance of risperidone and risperidone plus 9-hydroxyrisperidone was 13.7 L/h and 

5.0 L/h in extensive CYP 2D6 metabolizers, and 3.3 L/h and 3.2 L/h in poor CYP 2D6 

metabolizers, respectively. No accumulation of risperidone was observed during 

long-term use (up to 12 months) in patients treated every 2 weeks with 25 mg or 50 mg 

RISPERDAL ® CONSTA ® . The elimination phase is complete approximately 7 to 8 weeks 

after the last injection. 

Renal Impairment 

In patients with moderate to severe renal disease treated with oral RISPERDAL ® , 

clearance of the sum of risperidone and its active metabolite decreased by 60% 

compared with young healthy subjects. Although patients with renal impairment 

were not studied with RISPERDAL ® CONSTA ® , it is recommended that patients with 

renal impairment be carefully titrated on oral RISPERDAL ® before treatment with 

RISPERDAL ® CONSTA ® is initiated at a dose of 25 mg. A lower initial dose of 12.5 mg 

may be appropriate when clinical factors warrant dose adjustment, such as in 

patients with renal impairment [see Dosage and Administration (2.4)]. 

Hepatic Impairment 

While the pharmacokinetics of oral RISPERDAL ® in subjects with liver disease were 

comparable to those in young healthy subjects, the mean free fraction of risperidone 

in plasma was increased by about 35% because of the diminished concentration 

of both albumin and α1-acid glycoprotein. Although patients with hepatic 

impairment were not studied with RISPERDAL ® CONSTA ® , it is recommended that 

patients with hepatic impairment be carefully titrated on oral RISPERDAL ® before 

treatment with RISPERDAL ® CONSTA ® is initiated at a dose of 25 mg. A lower initial 

dose of 12.5 mg may be appropriate when clinical factors warrant dose adjustment, 

such as in patients with hepatic impairment [see Dosage and Administration (2.4)]. 

Elderly 

In an open-label trial, steady-state concentrations of risperidone plus 

9-hydroxyrisperidone in otherwise healthy elderly patients (≥ 65 years old) treated 

with RISPERDAL ® CONSTA ® for up to 12 months fell within the range of values 

observed in otherwise healthy nonelderly patients. Dosing recommendations are 

the same for otherwise healthy elderly patients and nonelderly patients [see Dosage 

and Administration (2)]. 

Race and Gender Effects 

No specific pharmacokinetic study was conducted to investigate race and gender 

effects, but a population pharmacokinetic analysis did not identify important 

differences in the disposition of risperidone due to gender (whether or not corrected 

for body weight) or race. 

13 NONCLINICAL TOXICOLOGY 

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 

Carcinogenesis - Oral 

Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. 

Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 

18 months to mice and for 25 months to rats. These doses are equivalent to 2.4, 9.4, 

and 37.5 times the oral maximum recommended human dose (MRHD) for 

schizophrenia (16 mg/day) on a mg/kg basis, or 0.2, 0.75, and 3 times the oral MRHD 

(mice) or 0.4, 1.5, and 6 times the oral MRHD (rats) on a mg/m2 basis. A maximum 

tolerated dose was not achieved in male mice. There was a significant increase in 

pituitary gland adenomas in female mice at doses 0.75 and 3 times the oral MRHD 

on a mg/m2 basis. There was a significant increase in endocrine pancreatic 

adenomas in male rats at doses 1.5 and 6 times the oral MRHD on a mg/m2 basis. 

Mammary gland adenocarcinomas were significantly increased in female mice at 

all doses tested (0.2, 0.75, and 3 times the oral MRHD on a mg/m2 basis), in female 

rats at all doses tested (0.4, 1.5, and 6 times the oral MRHD on a mg/m2 basis), and 

in male rats at a dose 6 times the oral MRHD on a mg/m2 basis. 

Carcinogenesis - Intramuscular 

RISPERDAL ® CONSTA ® was evaluated in a 24-month carcinogenicity study in which 

SPF Wistar rats were treated every 2 weeks with intramuscular (IM) injections of 

either 5 mg/kg or 40 mg/kg of risperidone. These doses are 1 and 8 times the MRHD 

(50 mg) on a mg/m2 basis. A control group received injections of 0.9% NaCl, and a 

vehicle control group was injected with placebo microspheres. There was a 

significant increase in pituitary gland adenomas, endocrine pancreas adenomas, 

and adrenomedullary pheochromocytomas at 8 times the IM MRHD on a mg/m2 basis. The incidence of mammary gland adenocarcinomas was significantly 

increased in female rats at both doses (1 and 8 times the IM MRHD on a mg/m2 basis). A significant increase in renal tubular tumors (adenoma, adenocarcinomas) 

was observed in male rats at 8 times the IM MRHD on a mg/m2 basis. Plasma 

exposures (AUC) in rats were 0.3 and 2 times (at 5 and 40 mg/kg, respectively) the 

expected plasma exposure (AUC) at the IM MRHD. 

Dopamine D2 receptor antagonists have been shown to chronically elevate prolactin 

levels in rodents. Serum prolactin levels were not measured during the 

carcinogenicity studies of oral risperidone; however, measurements taken during 

subchronic toxicity studies showed that oral risperidone elevated serum prolactin 

levels 5- to 6-fold in mice and rats at the same doses used in the oral carcinogenicity 

studies. Serum prolactin levels increased in a dose-dependent manner up to 6- and 

1.5-fold in male and female rats, respectively, at the end of the 24-month treatment 

with RISPERDAL ® CONSTA ® every 2 weeks. Increases in the incidence of pituitary 

gland, endocrine pancreas, and mammary gland neoplasms have been found in 

rodents after chronic administration of other antipsychotic drugs and may be 

prolactin-mediated. 

The relevance for human risk of the findings of prolactin-mediated endocrine tumors 

in rodents is unknown [see Warnings and Precautions (5.6)]. 

Mutagenesis 

No evidence of mutagenic potential for oral risperidone was found in the in vitro 

Ames reverse mutation test, in vitro mouse lymphoma assay, in vitro rat hepatocyte 

DNA-repair assay, in vivo oral micronucleus test in mice, the sex-linked recessive 

lethal test in Drosophila, or the in vitro chromosomal aberration test in human 

lymphocytes or in Chinese hamster cells. 

In addition, no evidence of mutagenic potential was found in the in vitro Ames 

reverse mutation test for RISPERDAL ® CONSTA ® . 

Impairment of Fertility 

Oral risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in 

Wistar rats in three reproductive studies (two mating and fertility studies and a 

multigenerational study) at doses 0.1 to 3 times the oral maximum recommended 

human dose (MRHD) (16 mg/day) on a mg/m2 basis. The effect appeared to be in 

females, since impaired mating behavior was not noted in the mating and fertility study 

in which males only were treated. In a subchronic study in Beagle dogs in which oral 

risperidone was administered at doses of 0.31 to 5 mg/kg, sperm motility and 

concentration were decreased at doses 0.6 to 10 times the oral MRHD on a mg/m2 basis. Dose-related decreases were also noted in serum testosterone at the same 

doses. Serum testosterone and sperm values partially recovered, but remained 

decreased after treatment was discontinued. No no-effect doses were noted in either 

rat or dog. 

No mating and fertility studies were conducted with RISPERDAL ® CONSTA ® . 

14 CLINICAL STUDIES 


The effectiveness of RISPERDAL ® CONSTA ® in the treatment of schizophrenia was 

established, in part, on the basis of extrapolation from the established effectiveness 

of the oral formulation of risperidone. In addition, the effectiveness of 

RISPERDAL ® CONSTA ® in the treatment of schizophrenia was established 

in a 12-week, placebo-controlled trial in adult psychotic inpatients and outpatients 

who met the DSM-IV criteria for schizophrenia. 

Efficacy data were obtained from 400 patients with schizophrenia who were 

randomized to receive injections of 25 mg, 50 mg, or 75 mg RISPERDAL ® CONSTA ® 

or placebo every 2 weeks. During a 1-week run-in period, patients were 

discontinued from other antipsychotics and were titrated to a dose of 4 mg oral 

RISPERDAL ® . Patients who received RISPERDAL ® CONSTA ® were given doses of 

oral RISPERDAL ® (2 mg for patients in the 25-mg group, 4 mg for patients in the 

50-mg group, and 6 mg for patients in the 75-mg group) for the 3 weeks after the 

first injection to provide therapeutic plasma concentrations until the main release 

phase of risperidone from the injection site had begun. Patients who received 

placebo injections were given placebo tablets. 

Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), 

a validated, multi-item inventory, composed of five subscales to evaluate positive 

symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/ 

excitement, and anxiety/depression. 

The primary efficacy variable in this trial was change from baseline to endpoint in 

the total PANSS score. The mean total PANSS score at baseline for schizophrenic 

patients in this study was 81.5.


Total PANSS scores showed significant improvement in the change from baseline to 

endpoint in schizophrenic patients treated with each dose of RISPERDAL ® CONSTA ® 

(25 mg, 50 mg, or 75 mg) compared with patients treated with placebo. While there 

were no statistically significant differences between the treatment effects for the three 

dose groups, the effect size for the 75 mg dose group was actually numerically less 

than that observed for the 50 mg dose group. 

Subgroup analyses did not indicate any differences in treatment outcome as a 

function of age, race, or gender. 

14.2 Bipolar Disorder - Monotherapy 

The effectiveness of RISPERDAL ® CONSTA ® for the maintenance treatment of 

Bipolar I Disorder was established in a multicenter, double-blind, placebo-controlled 

study of adult patients who met DSM-IV criteria for Bipolar Disorder Type I, who 

were stable on medications or experiencing an acute manic or mixed episode. 

A total of 501 patients were treated during a 26-week open-label period with 

RISPERDAL ® CONSTA ® (starting dose of 25 mg, and titrated, if deemed clinically 

desirable, to 37.5 mg or 50 mg; in patients not tolerating the 25 mg dose, the dose 

could be reduced to 12.5 mg). In the open-label phase, 303 (60%) patients were 

judged to be stable and were randomized to double-blind treatment with either the 

same dose of RISPERDAL ® CONSTA ® or placebo and monitored for relapse. The 

primary endpoint was time to relapse to any mood episode (depression, mania, 

hypomania, or mixed). 

Time to relapse was delayed in patients receiving RISPERDAL ® CONSTA ® 

monotherapy as compared to placebo. The majority of relapses were due to manic 

rather than depressive symptoms. Based on their bipolar disorder history, subjects 

entering this study had had, on average, more manic episodes than depressive 

episodes. 

14.3 Bipolar Disorder - Adjunctive Therapy 

The effectiveness of RISPERDAL ® CONSTA ® as an adjunct to treatment with lithium 

or valproate for the maintenance treatment of Bipolar Disorder was established in 

a multi-center, randomized, double-blind, placebo-controlled study of adult patients 

who met DSM-IV criteria for Bipolar Disorder Type I and who experienced at least 

4 episodes of mood disorder requiring psychiatric/clinical intervention in the 

previous 12 months, including at least 2 episodes in the 6 months prior to the start 

of the study. 

A total of 240 patients were treated during a 16-week open-label period with 

RISPERDAL ® CONSTA ® (starting dose of 25 mg, and titrated, if deemed clinically 

desirable, to 37.5 mg or 50 mg), as adjunctive therapy in addition to continuing their 

treatment as usual for their bipolar disorder, which consisted of mood stabilizers 

(primarily lithium and valproate), antidepressants, and/or anxiolytics. All oral 

antipsychotics were discontinued after the first three weeks of the initial 

RISPERDAL ® CONSTA ® injection. In the open-label phase, 124 (51.7%) were judged 

to be stable for at least the last 4 weeks and were randomized to double-blind 

treatment with either the same dose of RISPERDAL ® CONSTA ® or placebo in 

addition to continuing their treatment as usual and monitored for relapse during a 

52-week period. The primary endpoint was time to relapse to any new mood episode 

(depression, mania, hypomania, or mixed). 

Time to relapse was delayed in patients receiving adjunctive therapy with 

RISPERDAL ® CONSTA ® as compared to placebo. The relapse types were about half 

depressive and half manic or mixed episodes. 

16 HOW SUPPLIED/STORAGE AND HANDLING 

RISPERDAL ® CONSTA ® (risperidone) is available in dosage strengths of 12.5 mg, 

25 mg, 37.5 mg, or 50 mg risperidone. It is provided as a dose pack, consisting of a 

vial containing the risperidone microspheres, a pre-filled syringe containing 2 mL of 

diluent for RISPERDAL ® CONSTA ® , a SmartSite ® Needle-Free Vial Access Device, 

and two Needle-Pro ® safety needles for intramuscular injection (a 21 G UTW 1-inch 

needle with needle protection device for deltoid administration and a 20 G TW 2-inch 

needle with needle protection device for gluteal administration). 

12.5-mg vial/kit (NDC 50458-309-11): 41 mg (equivalent to 12.5 mg of risperidone) 

of a white to off-white powder provided in a vial with a violet flip-off cap 

(NDC 50458-309-01). 

25-mg vial/kit (NDC 50458-306-11): 78 mg (equivalent to 25 mg of risperidone) 

of a white to off-white powder provided in a vial with a pink flip-off cap 

(NDC 50458-306-01). 

37.5-mg vial/kit (NDC 50458-307-11): 116 mg (equivalent to 37.5 mg of risperidone) 

of a white to off-white powder provided in a vial with a green flip-off cap 

(NDC 50458-307-01). 

50-mg vial/kit (NDC 50458-308-11): 152 mg (equivalent to 50 mg of risperidone) of a 

white to off-white powder provided in a vial with a blue flip-off cap 

(NDC 50458-308-01). 

Storage and Handling 

The entire dose pack should be stored in the refrigerator (36°-46°F; 2°-8°C) and 

protected from light. 

If refrigeration is unavailable, RISPERDAL ® CONSTA ® can be stored at temperatures 

not exceeding 77°F (25°C) for no more than 7 days prior to administration. Do not 

expose unrefrigerated product to temperatures above 77°F (25°C). 

Keep out of reach of children. 

17 PATIENT COUNSELING INFORMATION 

Physicians are advised to discuss the following issues with patients for whom they 

prescribe RISPERDAL ® CONSTA ® . 


Patients should be advised of the risk of orthostatic hypotension and instructed in 

nonpharmacologic interventions that help to reduce the occurrence of orthostatic 

hypotension (e.g., sitting on the edge of the bed for several minutes before 

attempting to stand in the morning and slowly rising from a seated position) [see 

Warnings and Precautions (5.7)]. 

17.2 Interference with Cognitive and Motor Performance 

Because RISPERDAL ® CONSTA ® has the potential to impair judgment, thinking, or 

motor skills, patients should be cautioned about operating hazardous machinery, 

including automobiles, until they are reasonably certain that treatment with 

RISPERDAL ® CONSTA ® does not affect them adversely [see Warnings and 

Precautions (5.9)]. 

17.3 Pregnancy 

Patients should be advised to notify their physician if they become pregnant or 

intend to become pregnant during therapy and for at least 12 weeks after the last 

injection of RISPERDAL ® CONSTA ® [see Use in Specific Populations (8.1)]. 

17.4 Nursing 

Patients should be advised not to breast-feed an infant during treatment and for at 

least 12 weeks after the last injection of RISPERDAL ® CONSTA ® [see Use in Specific 

Populations (8.3)]. 

17.5 Concomitant Medication 

Patients should be advised to inform their physicians if they are taking, or plan to 

take, any prescription or over-the-counter drugs, since there is a potential for 

interactions [see Drug Interactions (7)]. 

17.6 Alcohol 

Patients should be advised to avoid alcohol during treatment with 

RISPERDAL ® CONSTA ® [see Drug Interactions (7.1)]. 

10130505 

Revised April 2010 

© Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2007 

Risperidone is manufactured by: 

Janssen Pharmaceutical Ltd. 

Wallingstown, Little Island, County Cork, Ireland 

Microspheres are manufactured by: 

Alkermes, Inc. 

Wilmington, Ohio 

Diluent is manufactured by: 

Vetter Pharma Fertigung GmbH & Co. KG 

Ravensburg or Langenargen, Germany or 

Cilag AG 

Schaffhausen, Switzerland or 

Ortho Biotech Products, L.P. 

Raritan, NJ 

RISPERDAL ® CONSTA ® is manufactured for: 

Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. 

Titusville, NJ 08560

AVERAGE SALES PRICE (ASP) FOR MEDICARE ... - Janssen CNS

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